Method for synthesizing 5beta, 6beta-epoxides of steroids by a highly beta-selective epoxidation of delta5-unsaturated steroids catalyzed by ketones

ABSTRACT

A general, efficient, and environmentally friendly method is provided for producing mostly β-epoxides of Δ 5 -unsaturated steroids using certain ketones as the catalyst along with an oxidizing agent, or by using certain dioxiranes. In another aspect of the invention, a method is provided for producing mostly 5β,6β-epoxides of steroids from Δ 5 -unsaturated steroids having a substituent at the 3α-position by an epoxidation reaction using a ketone along with an oxidizing agent under conditions effective to generate epoxides, or using a dioxirane under conditions effective to generate epoxides. A whole range of Δ 5 -unsaturated steroids, bearing different functional groups such as hydroxy, carbonyl, acetyl or ketal group as well as different side chains, were conveniently converted to the corresponding synthetically and biologically interesting 5β,6β-epoxides with excellent β-selectivities and high yields.

[0001] This application is a continuation-in-part of non-provisionalapplication Ser. No. 09/788,201 filed Feb. 16, 2001, which claims thebenefit under 35 U.S.C. 119(e) of U.S. Provisional Application SerialNo. 60/183,396 filed Feb. 18, 2000.

TECHNICAL FIELD

[0002] The present invention is directed to the field of synthesizingepoxides of steroids.

BACKGROUND OF THE INVENTION

[0003] Steroid epoxides are an important class of oxysterols (oxygenatedderivatives of cholesterol) involved in the regulation of cellproliferation and cholesterol homeostasis. They are versatileintermediates for steroid synthesis and useful probes for biochemicalstudies of enzymes. Steroid epoxides are also useful intermediates forthe preparation of other oxysterols. For example, α- and β-epoxides ofcholesterol are auto-oxidation products of cholesterol in vivo, and bothare cytotoxic and mutagenic. The isomeric α- and β-epoxides arehydrolysed by cholesterol 5,6-epoxide hydrolase tocholestane-3β,5α,6β-triol which has potent hypocholesterolemic activity.On the other hand, both epoxides inhibit the cholesterol 7α-hydroxylasewhich catalyzes the rate-determining step of bile acid synthesis. As5α,6α-epoxides are readily available via epoxidation of Δ⁵-unsaturatedsteroids with peracids, there have been extensive studies on thebiological actions of those epoxides and their derivatives. In contrast,much less is known about the 5β,6β-epoxides and their derivativesbecause they are difficult to obtain in high selectivity. Moreimportantly, the 5β,6β-epoxy functionality is found in a number ofnaturally occurring steroids of antitumor activities, e.g.,jaborosalactone A, withaferin A, and withanolide D.

[0004] Common organic oxidants such as 3-chloroperoxybenzoic acid(mCPBA) generally give α-epoxides as the major products for epoxidationof 3β-substituted Δ⁵-steroids and show poor selectivities forepoxidation of 3α-substituted Δ⁵-steroids except epi-cholesterol. Thisis because peracid epoxidation follows a concerted pathway via spirotransition states (α-TS and β-TS (TS=transition state); see FIG. 1). Theβ-TS suffers from steric interactions between the peracid and the C(10)angular methyl group for epoxidation of 3β-substituted Δ⁵-steroids,while both the β-TS and the α-TS encounter similar steric hindrance forepoxidation of 3α-substituted Δ⁵-steroids. Dioxiranes are new-generationreagents for oxidation under mild and neutral conditions. Unfortunately,poor selectivities were reported in epoxidation of 3β-substitutedΔ⁵-steroids by either isolated or in situ generated dioxiranes. Whiledioxiranes also epoxidize olefins through a spiro TS, their stericenvironment is different from that of peracids. To minimize stericinteractions, dioxiranes prefer to approach the C(5)═C(6) double bond ofΔ⁵-steroids from the less-substituted side, i.e., away from theC(10)-angular methyl group and the C-ring of steroids (FIG. 1).Therefore, it is the potential steric interactions between theα-substituents of dioxiranes and the 3α and 4β substituents of steroidsthat determine the facial selectivity of epoxidation.

[0005] Yang et al., in U.S. Pat. No. 5,763,623 and in J. Org. Chem.,1998, vol. 63 pages 8952-8956, disclose the epoxidation ofunfunctionalized olefins using various ketones. These references do notteach or suggest the epoxidation of Δ⁵-unsaturated steroids.

[0006] Cicala, G., et al., J. Org. Chem., 1982, vol. 47, pages2670-2673, disclose the epoxidation of a Δ⁵-unsaturated steroid that isnot a 3α-substituted Δ⁵-unsaturated steroid, and in which the ketonecatalyst is acetone.

[0007] Marples, B. A., et al. Tetrahedron Lett., 1991, vol. 32, pages533-536, disclose the epoxidation reactions of four Δ⁵-unsaturatedsteroids that are not 3ax-substituted Δ⁵-unsaturated steroids, and usinga variety of ketones. In these reactions either no epoxide was observed,or the β/α-epoxide ratio was about 1:1.

[0008] Bovicelli, P., et al., J. Org. Chem., 1992, vol. 57, pages2182-2184, disclose the epoxidation of a Δ⁵-unsaturated steroid that isnot a 3α-substituted Δ⁵-unsaturated steroid, and usingdimethyldioxirane. The β/α-epoxide ratio was about 3:1.

[0009] Boehlow, T. R., et al., Tetrahedron Lett., 1998, vol. 39, pages1839-1842, disclose the epoxidation of a Δ⁵-unsaturated steroid that isnot a 3α-substituted Δ⁵-unsaturated steroid, and using a variety ofketone catalysts.

[0010] Shi, Y., in PCT Publication No. WO 01/12616 A1, Feb. 22, 2001,discloses an epoxidation method combining an olefin substrate, a ketonecatalyst, a nitrile compound, and hydrogen peroxide.

[0011] Shi, Y., in PCT Publication No. WO 98/15544, Apr. 16, 1998,discloses the use of a chiral ketal and an oxidizing agent with anolefin to generate an epoxide with high enantioselectricity.

SUMMARY OF THE INVENTION

[0012] In accordance with the invention, a method is provided forproducing mostly 5β,6β-epoxides of Δ⁵-unsaturated steroids using certainketones as the catalyst along with an oxidizing agent, or by usingcertain dioxiranes. In another aspect of the invention, a method isprovided for producing mostly 5β,6β-epoxides of steroids fromΔ⁵-unsaturated steroids having a substituent at the 3α-position by anepoxidation reaction using a ketone along with an oxidizing agent underconditions effective to generate epoxides, or using a dioxirane underconditions effective to generate epoxides.

[0013] A whole range of Δ⁵-unsaturated steroids, bearing differentfunctional groups such as hydroxy, carbonyl, acetyl or ketal group, aswell as different side chains, are converted to the correspondingsynthetically and biologically interesting 5β,6β-epoxides with excellentβ-selectivities and high yields.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014]FIG. 1 is a diagrammatic representation of the general epoxidationreaction between Δ⁵-unsaturated steroids and mCPBA or dioxirane;

[0015]FIG. 2 is a listing of chemical structures corresponding toketones 1-4 and steroids 5-20;

[0016]FIG. 3 is a diagrammatic representation of the epoxidationreaction of the present invention; and

[0017] FIGS. 4-70 are ¹H NMR spectra of 5,β,6β-epoxides of steroids and5α,6α-epoxides of steroids including those epoxides of steroidssynthesized as products by the method of the present invention andpurified epoxides of steroids used as comparative control standards(referred to as “authentic samples”).

DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention provides highly β-selective epoxidation ofΔ⁵-unsaturated steroids catalyzed by ketones or mediated by dioxiranes.More specifically, the present invention demonstrates that highβ-selectivity can be achieved by increasing the steric size of eitherthe α-substituents of dioxiranes or the 3α substituents of Δ⁵-steroids.In some embodiments of the invention, the epoxidation reaction canprovide said epoxides in at least about 5:1β/α-epoxide ratio.

[0019] In one aspect of the invention, a method of producing mostly5β,6β-epoxides of steroids from Δ⁵-unsaturated steroids comprises anepoxidation reaction using a ketone and an oxidizing agent underconditions effective to generate epoxides, wherein the ketone isselected from compounds of generic formula I,

[0020] in which R₁ or R₄ in formula (I) is selected from alkyl,halogenated alkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H,alkyl or aryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl),OCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ orR₃=alkyl or aryl), and halogen;

[0021] R₂ or R₃ in formula (I) is selected from H, alkyl, halogenatedalkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H, alkyl oraryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl), OCONR₁R₂(where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkylor aryl), and halogen;

[0022] R₅, R₆, R₇ or R₈ in formula (I) is selected from H, alkyl,halogenated alkyl, aryl, COOR (where R=H, alkyl or aryl), and CONR₁R₂(where R₁ or R₂=H, alkyl or aryl);

[0023] R₉ or R₁₀ in formula (I) is selected from alkyl, halogenatedalkyl, and aryl; and

[0024] A in formula (I) is selected from halogen, OTf, BF₄, OAc, NO₃,BPh₄, PF₆, and SbF₆.

[0025] In another aspect of the invention, a method of producing mostly5β,6β-epoxides of steroids from Δ⁵-unsaturated steroids having asubstituent at the 3α-position comprises an epoxidation reaction using aketone and an oxidizing agent under conditions effective to generateepoxides. The substituent at the 3α-position can be selected from OR(where R=H, alkyl or arly), O(CH₂)_(n)OR (where n=1, 2 or 3, R=H, alkylor aryl), O(CH₂)_(m)SO_(n)R (where n=1, 2 or 3; n=0, 1 or 2; R=H, alkylor aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkyl or aryl), OSO_(n)R wheren=0, 1 or 2; R=H, alkyl or aryl), OCO_(n)R (where n=1 or 2; R=H, alkylor aryl), OCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl), OPO_(n)R (wherewhere n=2 or 3; R=alkyl or arly), NR₁R₂ (where R₁ or R₂=H, alkyl oraryl), NR₁CO_(n)R₂ (where n=1 or 2; R₁ or R₂=H, alkyl or aryl),NR₁CONR₂R₃ (where R₁, R₂ or R₃=H, alkyl or aryl), NR₁SO_(n)R₂ (where n=1or 2; R₁=H, alkyl or aryl, R₂=alkyl or aryl), NPhth (Phth=phthaloylgroup), ⁺NR₁R₂R₃ (where R₁, R₂, or R₃=H, alkyl or aryl), SiR₁R₂R₃ (whereR₁, R₂, or R₃=H, alkyl or aryl), SO_(n)R (where n=0, 1 or 2; R=H, alkylor aryl), SCO_(n)R (where n=1 or 2; R=H, alkyl or aryl), halogen, CN,NO₂, alkyl, aryl, COOR (where R=H, alkyl or aryl), and CONR₁R₂ (where R₁or R₂=H, alkyl or arly).

[0026] Further in accordance with this aspect of the invention, theΔ⁵-unsaturated steroid having a substituent at the 3α-position can beselected from the group consisting of Δ⁵-unsaturated steroids having aketal derivative of ketone group or a thioketal derivative of ketonegroup at the 3-position.

[0027] Further in accordance with this aspect of the invention, theketone used in the epoxidation reaction can be selected from the groupconsisting of compounds of generic formula II, III, IV, and V wherein

[0028] R₁, R₂, R₃, or R₄ in formula (II) is selected from H, alkyl,halogenated alkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H,alkyl or aryl), OCOOR (where R=alkyl or aryl), OCONR₁R₂ (where R₁ orR₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkyl or aryl), andhalogen;

[0029] R₅, R₆, R₇, R₈, R₉ or R₁₀ in formula (II) is selected from H,alkyl, halogenated alkyl, aryl, COOR (where R=H, alkyl or aryl), andCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl);

[0030] A in formula (iI) is selected from halogen, OTf, BF₄, OAc, NO₃,BPh₄, PF₆, and SbF₆;

[0031] X in formula (III) is selected from (CR₁R₂)_(n) (where n=1, 2, 3,4, or 5; R₁ or R₂=H, alkyl or aryl), O, S, SO, SO₂, and NR (where R=H,alkyl or aryl);

[0032] R₁₁, R₁₂, R₁₃, or R₁₄ in formula (III) is selected from H, alkyl,halogenated alkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H,alkyl or aryl), OCOOR (where R=alkyl or aryl), OCONR₁R₂ (where R₁ orR₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkyl or aryl), andhalogen;

[0033] R₁₅, R₁₆, R₁₇, or R₁₈ in formula (III) is selected from H, alkyl,halogenated alkyl, aryl, COOR (where R=H, alkyl or aryl), and CONR₁R₂(where R₁ or R₂=H, alkyl or aryl);

[0034] R₁₉ or R₂₀ in formula (IV) is selected from alkyl, halogenatedalkyl, aryl, CR₁R₂OCOR₃ (where R₁, R₂ or R₃=H, alkyl or aryl),CR₁R₂OCOOR₃ (where R₁ or R₂=H, alkyl or aryl; R₃=alkyl or aryl),CR₁R₂NR₃COOR₄ (where R₁, R₂ or R₃=H, alkyl or aryl, R₄=alkyl or aryl),CR₁R₂NR₃COR₄ (where R₁, R₂, R₃ or R₄=H, alkyl or aryl), andCR₁R₂NR₃SO₂R₄ (where R₁, R₂ or R₃=H, alkyl or aryl; R₄=alkyl or aryl);and

[0035] Y in formula (V) is selected from H, alkyl, halogenated alkyl,aryl, NO₂, CN, F, Cl, Br, I, COOR (where R=H or alkyl), OR (where R=H,alkyl or aryl), OSO₂R (where R=H, alkyl or aryl), OSOR (where R=H, alkylor aryl), OSR (where R=H, alkyl or aryl), S0₂R (where R=H, alkyl oraryl), SO₃R (where R=H, alkyl or aryl), SOON R₁R₂ (where R₁ or R₂=H,alkyl or aryl), NR₁SOOR₂ (where R₁=H, alkyl or aryl; R₂=alkyl or aryl),NR₁SOR₂ (where R₁=H, alkyl or aryl; R₂=alkyl or aryl), CR₁R₂OR₃ (whereR₁, R₂ or R₃=H, alkyl or aryl), CR₁(OR₂)₂ (where R₁=H or alkyl;R₂=alkyl), CF₃, CF₂CF₃, OTf, OTs, OCOR (where R=H, alkyl or aryl), andOSiR₁R₂R₃ (where R₁, R₂ or R₃=alkyl or aryl).

[0036] In yet another aspect of the invention, a method of producingmostly 5,6β-epoxides of steroids from Δ⁵-unsaturated steroids comprisesan epoxidation reaction using a dioxirane under conditions effective togenerate epoxides, wherein said dioxirane is selected from compounds ofgeneric formula VI,

[0037] R₁ or R₄ in formula (VI) is selected from alkyl, halogenatedalkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H, alkyl oraryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl), OCONR₁R₂(where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkylor aryl), and halogen;

[0038] R₂ or R₃ in formula (VI) is selected from H, alkyl, halogenatedalkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H, alkyl oraryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl), OCONR₁R₂(where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkylor aryl), and halogen;

[0039] R₅, R₆, R₇ or R₈ in formula (VI) is selected from H, alkyl,halogenated alkyl, aryl, COOR (where R=H, alkyl or aryl), and CONR₁R₂(where R₁ or R₂=H, alkyl or aryl);

[0040] R₉ or R₁₀ in formula (VI) is selected from alkyl, halogenatedalkyl, and aryl; and

[0041] A in formula (VI) is selected from halogen, OTf, BF₄, OAc, NO₃,BPh4, PF₆, and SbF₆.

[0042] The dioxirane can be generated in situ from a ketone and anoxidizing agent selected from potassium peroxomonosulfate, sodiumhypochlorite, sodium perborate, hydrogen peroxide, and peracids, whereinsaid ketone is selected from compounds of generic formula I,

[0043] R₁ or R₄ in formula (I) is selected from alkyl, halogenatedalkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H, alkyl oraryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl), OCONR₁R₂(where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkylor aryl), and halogen;

[0044] R₂ or R₃ in formula (I) is selected from H, alkyl, halogenatedalkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H, alkyl oraryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl), OCONR₁R₂(where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkylor aryl), and halogen;

[0045] R₅, R₆, R₇ or R₈ in formula (I) is selected from H, alkyl,halogenated alkyl, aryl, COOR (where R=H, alkyl or aryl), and CONR₁R₂(where R₁ or R₂=H, alkyl or aryl);

[0046] R₉ or R₁₀ in formula (I) is selected from alkyl, halogenatedalkyl, and aryl; and

[0047] A in formula (I) is selected from halogen, OTf, BF₄, OAc, NO₃,BPh₄, PF₆, and SbF₆.

[0048] In yet another aspect of the invention, a method of producingmostly 5β,6β-epoxides of steroids from Δ⁵-unsaturated steroids having asubstituent at the 3α-position comprises an epoxidation reaction using adioxirane under conditions effective to generate epoxides. In accordancewith this aspect of the invention, the substituent at the 3α-positioncan be selected from OR (where R=H, alkyl or aryl), O(CH₂)_(n)OR (wheren=1, 2 or 3, R=H, alkyl or aryl), O(CH₂)_(m)SO_(n)R (where n=1, 2 or 3;n=0, 1 or 2; R=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkyl oraryl), OSO_(n)R (where n=0, 1 or 2; R=H, alkyl or aryl), OCO_(n)R (wheren=1 or 2; R=H, alkyl or aryl), OCONR₁R₂ (where R₁ or R₂=H, alkyl oraryl), OPO_(n)R (where where n=2 or 3; R=alkyl or aryl), NR₁R₂ (where R₁or R₂=H, alkyl or aryl), NR₁CO_(n)R₂ (where n=1 or 2; R₁ or R₂=H, alkylor aryl), NR₁CONR₂R₃ (where R₁, R₂ or R₃=H, alkyl or aryl), NR₁SO_(n)R₂(where n=1 or 2; R₁=H, alkyl or aryl, R₂=alkyl or aryl), NPhth(Phth=phthaloyl group), ⁺NR₁R₂R₃ (where R₁, R₂, or R₃=H, alkyl or aryl),SiR₁R₂R₃ (where R₁, R₂, or R₃=H, alkyl or aryl), SO_(n)R (where n=0, 1or 2; R=H, alkyl or aryl), SCO_(n)R (where n=1 or 2; R=H, alkyl oraryl), halogen, CN, NO₂, alkyl, aryl, COOR (where R=H, alkyl or aryl),and CONR₁R₂ (where R₁ or R₂=H, alkyl or aryl).

[0049] Further in accordance with this aspect of the invention, theΔ⁵-unsaturated steroid having a substituent at the 3α-position can beselected from the group consisting of Δ⁵-unsaturated steroids having aketal derivative of a ketone group or a thioketal derivative of a ketonegroup at the 3-position.

[0050] Further in accordance with this aspect of the invention, thedioxirane can be selected from the group consisting of compounds ofgeneric formula VII, VIII, IX and X.

[0051] R₁, R₂, R₃, or R₄ in formula (VII) is selected from H, alkyl,halogenated alkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H,alkyl or aryl), OCOOR (where R=alkyl or aryl), OCCOOCH₂R (where R=aryl),OCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ orR₃=alkyl or aryl), and halogen;

[0052] R₅, R₆, R₇, R₈, R₉ or R₁₀, in formula (VII) is selected from H,alkyl, halogenated alkyl, aryl, COOR (where R=H, alkyl or aryl), andCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl);

[0053] A in formula (VII) is selected from halogen, OTf, BF₄, OAc, NO₃,BPh₄, PF₆, and SbF₆;

[0054] X in formula (VIII) is selected from (CR₁R₂)_(n), (where n=1, 2,3, 4, or 5; R₁ or R₂=H, alkyl or aryl), O, S, SO, SO₂, and NR (whereR=H, alkyl or aryl);

[0055] R₁₁, R₁₂, R₁₃, or R₁₄ in formula (VIII) is selected from H,alkyl, halogenated alkyl, aryl, OR (where R=H, alkyl or aryl), OCOR(where R=H, alkyl or aryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R(where R=aryl), OCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃(where R₁, R₂ or R₃=alkyl or aryl), and halogen;

[0056] R₁₅, R₁₆, R₁₇, or R₁₈ in formula (VIII) is selected from H,alkyl, halogenated alkyl, aryl, COOR (where R=H, alkyl or aryl), andCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl);

[0057] R₁₉ or R₂₀ in formula (IX) is selected from alkyl, halogenatedalkyl, aryl, CR₁R₂OCOR₃ (where R₁, R₂ or R₃=H, alkyl or aryl),CR₁R₂OCOOR₃ (where R₁ or R₂=H, alkyl or aryl; R₃=alkyl or aryl),CR₁R₂NR₃COOR₄ (where R₁, R₂ or R₃=H, alkyl or aryl, R₄=alkyl or aryl),CR₁R₂NR₃COR₄ (where R₁, R₂, R₃ or R₄=H, alkyl or aryl), CR₁R₂NR₃SO₂R₄(where R₁, R₂ or R₃=H, alkyl or aryl; R₄=alkyl or aryl); and

[0058] Y in formula (X) is selected from H, alkyl, halogenated alkyl,aryl, NO₂, CN, F, Cl, Br, I, COOR (where R=H or alkyl), OR (where R=H,alkyl or aryl), OSO₂R (where R=H, alkyl or aryl), OSOR (where R=H, alkylor aryl), OSR (where R=H, alkyl or aryl), SO₂R (where R=H, alkyl oraryl), SO₃R (where R=H, alkyl or aryl), SOON R₁R₂ (where R₁ or R₂=H,alkyl or aryl), NR₁SOOR₂ (where R₁=H, alkyl or aryl; R₂=alkyl or aryl),NR₁SOR₂ (where R₁=H, alkyl or aryl; R₂=alkyl or aryl), CR₁R₂OR₃ (whereR_(1, R) ₂ or R₃=H, alkyl or aryl), CR₁(OR₂)₂ (where R₁=H or alkyl;R₂=alkyl), CF₃, CF₂CF₃, OTf, OTs, OCOR (where R=H, alkyl or aryl), andOSiR₁R₂R₃ (where R₁, R₂ or R₃=alkyl or aryl).

[0059] The dioxirane can be generated in situ from a ketone and anoxidizing agent selected from potassium peroxomonosulfate, sodiumhypochlorite, sodium perborate, hydrogen peroxide, and peracids. In suchembodiments of the invention, the ketone can be selected from the groupconsisting of compounds of generic formula II, III, IV, and V,

[0060] R₁, R₂, R₃, or R₄ in formula (II) is selected from H, alkyl,halogenated alkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H,alkyl or aryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl),OCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ orR₃=alkyl or aryl), and halogen;

[0061] R₅, R₆, R₇, R₈, R₉ or R₁₀ in formula (II) is selected from H,alkyl, halogenated alkyl, aryl, COOR (where R=H, alkyl or aryl), andCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl);

[0062] A in formula (II) is selected from halogen, OTf, BF₄, OAc, NO₃,BPh₄, PF₆, and SbF₆;

[0063] X in formula (III) is selected from (CR₁R₂)_(n) (where n=1, 2, 3,4, or 5; R₁ or R₂=H, alkyl or aryl), O, S, SO, SO₂, and NR (where R=H,alkyl or aryl);

[0064] R₁₁, R₁₂, R₁₃, or R₁₄ in formula (III) is selected from H, alkyl,halogenated alkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H,alkyl or aryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl),OCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ orR₃=alkyl or aryl), and halogen;

[0065] R₁₅, R₁₆, R₁₇, or R₁₈ in formula (III) is selected from H, alkyl,halogenated alkyl, aryl, COOR (where R=H, alkyl or aryl), and CONR₁R₂(where R₁ or R₂=H, alkyl or aryl);

[0066] R₁₉ or R₂₀ in formula (IV) is selected from alkyl, halogenatedalkyl, aryl, CR₁R₂OCOR₃ (where R_(1, R) ₂ or R₃=H, alkyl or aryl),CR₁R₂OCOOR₃ (where R₁ or R₂=H, alkyl or aryl; R₃=alkyl or aryl),CR₁R₂NR₃COOR₄ (where R₁, R₂ or R₃=H, alkyl or aryl, R₄=alkyl or aryl),CR₁R₂NR₃COR₄ (where R₁, R₂, R₃ or R₄=H, alkyl or atyl), CR₁R₂NR₃SO₂R₄(where R₁, R₂ or R₃=H, alkyl or aryl; R₄=alkyl or aryl); and

[0067] Y in formula (V) is selected from H, alkyl, halogenated alkyl,aryl, NO₂, CN, F, Cl, Br, I, COOR (where R=H or alkyl), OR (where R=H,alkyl or aryl), OSO₂R (where R=H, alkyl or aryl), OSOR (where R=H, alkylor aryl), OSR (where R=H, alkyl or aryl), SO₂R (where R=H, alkyl oraryl), SO₃R (where R=H, alkyl or aryl), SOON R₁R₂ (where R₁ or R₂=H,alkyl or aryl), NR₁SOOR₂ (where R₁=H, alkyl or aryl; R₂=alkyl or aryl),NR₁SOR₂ (where R₁=H, alkyl or aryl; R₂=alkyl or aryl), CR₁R₂OR₃ (whereR₁, R₂ or R₃=H, alkyl or aryl), CR₁(OR₂)₂ (where R₁=H or alkyl;R₂=alkyl), CF₃, CF₂CF₃, OTf, OTs, OCOR (where R=H, alkyl or aryl), andOSiR₁R₂R₃ (where R₁, R₂ or R₃=alkyl or aryl).

[0068] Epoxidation reactions in accordance with the invention and usingdioxiranes can be carried out in a solvent selected from acetonitrile,dimethoxymethane, acetone, dioxane, dimethoxyethane, tetrahydrofuran,dichloromethane, chloroform, benzene, toluene, diethylether, water andmixtures thereof.

[0069] In accordance with one embodiment of the invention herein, amethod of producing mostly 5β,6β-epoxides of steroids comprisesepoxidation reactions of Δ⁵-unsaturated steroids of generic formula XIcatalyzed by ketones of generic formula XII, wherein

[0070] X₁ in formula (XI) is selected from H, OR (where R=H or alkyl),OCH₂OCH₃, OCOR (where R=alkyl or aryl), OSiR₁′R₂′R₃′ (where R₁′, R₂′ orR₃′=alkyl or aryl), halogen, CN, alkyl, aryl, and COOR (where R=H, alkylor aryl);

[0071] R₁ in formula (XI) is selected from H, OR (where R=H or alkyl),OCOR (where R=alkyl or aryl), OCH₂OCH₃, halogen, CF₃, and CF₂CF₃;

[0072] R₂ and R₃ in formula (XI) are each selected from the groupconsisting of H, alkyl, aryl, halogen, OR (where R=H or alkyl), OCOR(where R=alkyl or aryl), OSiR₁′R₂′R₃′ (where R₁′, R₂′ or R₃′=alkyl oraryl), COR (where R=alkyl), COCH₂OR (where R=H or alkyl), COCH₂OCOR(where R=alkyl or aryl), COCH₂F, COOR (where R=H or alkyl), C(OCH₂CH₂O)R(where R=alkyl), C(OCH₂CH₂)CH₂OR (where R=H or alkyl),C(OCH₂CH₂O)CH₂OCOR (where R=alkyl or aryl), and C(OCH₂CH₂O)CH₂F; or, areselected from the group consisting of O, OCH₂CH₂O, and OCH₂CH₂CH₂O;

[0073] R₄ in formula (XI) is selected from H, C₁-C₄ alkyl, halogen, OR(where R=H or alkyl), OCOR (where R=alkyl or aryl), and OSiR₁′R₂′R₃′(where R₁′, R₂′ or R₃′=alkyl or aryl);

[0074] R₅ in formula (XI) is selected from H, C₁-C₄ alkyl, halogen, OR(where R=H or alkyl), OCOR (where R=alkyl or aryl), and OSiR₁′R₂′R₃′(where R₁′, R₂′ or R₃′=alkyl or aryl);

[0075] R₆ in formula (XI) is selected from H, halogen, OR (where R=H oralkyl), and OCOR (where R=alkyl or aryl);

[0076] R₇ in formula (XI) is selected from H, halogen, OR (where R=H oralkyl), and OCOR (where R=alkyl or aryl);

[0077] R₁₅ and R₁₆ in formula (XII) are each selected from alkyl andaryl;

[0078] R₁₇ and R₁₈ in formula (XII) are each selected from H, alkyl,aryl, COOR (where R=H, alkyl or aryl), and CONR₁R₂ (where R₁ or R₂=H,alkyl or aryl);

[0079] R₁₉ and R₂₀ in formula (XII) are each selected from C₁-C₄ alkyl,halogenated alkyl, and halogen; and

[0080] A in formula (XII) is selected from OTf, BF₄, OAc, NO₃, BPh₄,PF₆, and SbF₆.

[0081] In another embodiment of the instant invention, a method ofproducing mostly 5β,662-epoxides of steroids comprises epoxidationreactions of Δ⁵-unsaturated steroids of generic formula XIII catalyzedby ketones of generic formula XIV, XV, XVI, and XVII, wherein

[0082] X₂ in formula (XIII) is selected from the group consisting of H,OR (where R=H or alkyl), OCH₂OCH₃, OCOR (where R=alkyl or aryl),OSiR₁′R₂′R₃′ (where R₁′, R₂′ or R₃′=alkyl or aryl), halogen, CN, alkyl,aryl, and COOR (where R=H, alkyl or aryl), and,

[0083] X₃ in formula (XIII) is selected from the group consisting of OR(where R=H or alkyl), OCH₂OCH₃, OCOR (where R=alkyl or aryl),OSiR₁′R₂′R₃′ (where R₁ 40 , R₂′ or R₃′=alkyl or aryl), halogen, CN, NO₂,alkyl, and aryl; or,

[0084] X₂ and X₃ in formula (XIII) are selected from the groupconsisting of O, OCH₂CH₂O, and OCH₂CH₂CH₂O;

[0085] R₈ in formula (XIII) is selected from H, OR (where R=H or alkyl),OCOR (where R=alkyl or aryl), OCH₂OCH₃, halogen, CF₃, and CF₂CF₃;

[0086] R₉ and R₁₀ in formula (XIII) are each selected from the groupconsisting of H, alkyl, aryl, halogen, OR (where R=H or alkyl), OCOR(where R=alkyl or aryl), OSiR₁′R₂′R₃′ (where R₁′, R₂′ or R₃′=alkyl oraryl), COR (where R=alkyl), COCH₂OR (where R=H or alkyl), COCH₂OCOR(where R=alkyl or aryl), COCH₂F, COOR (where R=H or alkyl), C(OCH₂CH₂O)R(where R=alkyl), C(OCH₂CH₂O)CH₂OR (where R=H or alkyl),C(OCH₂CH₂O)CH₂OCOR (where R=alkyl or aryl), and C(OCH₂CH₂O)CH₂F; or R₉and R₁₀ in formula (XIII) are selected from the group consisting of O,OCH₂CH₂O, and OCH₂CH₂CH₂O;

[0087] R₁₁ and R₁₂ in formula (XIII) are each selected from the groupconsisting of H, C₁-C₄ alkyl halogen, OR (where R=H or alkyl), OCOR(where R=alkyl or aryl), and OSiR₁′R₂′R₃′ (where R₁′, R₂′ or R₃′=alkylor aryl);

[0088] R₁₃ and R₁₄ in formula (XIII) are each selected from the groupconsisting of H, halogen, OR (where R=H or alkyl), and OCOR (whereR=alkyl or aryl);

[0089] R₁₅ or R₁₆ in formula (XIV) is selected from alkyl and aryl;

[0090] R₁₇ or R₁₈ in formula (XIV) is selected from H, alkyl, aryl, COOR(where R=H, alkyl or aryl), and CONR₁R₂ (where R₁ or R₂=H, alkyl oraryl);

[0091] R₁₉ or R₂₀ in formula (XIV) is selected from H, C₁-C₄ alkyl,halogenated alkyl, and halogen; and

[0092] A in formula (XIV) is selected from OTf, BF₄, OAc, NO₃, BPh₄,PF₆, and SbF₆;

[0093] Y in formula (XV) is selected from CH₂, O, S, SO, SO₂, and NR(where R=H or alkyl);

[0094] R₂₁ or R₂₂ in formula (XV) is selected from H, alkyl, aryl, COOR(where R=H, alkyl or aryl), and CONR₁R₂ (where R₁or R₂=H, alkyl oraryl);

[0095] R₂₃ or R₂₄ in formula (XV) is selected from H, halogen, C₁-C₄alkyl, halogenated alkyl, and OCOR (where R=alkyl or aryl);

[0096] R₂₅ or R₂₆ in formula (XVI) is selected from C₁-C₄ alkyl,halogenated alkyl, CH₂OCOR (where R=alkyl or aryl); and

[0097] Z in formula (XVII) is selected from H, C₁-C₄ alkyl, aryl, NO₂,CN, F, Cl, Br, I, COOR (where R=alkyl), CH₂OR (where R=H or alkyl),CH(OR)₂ (where R=alkyl), CF₃, CF₂CF₃, OTf, OTs, OCOR (where R=alkyl oraryl), and OSiR₁′R₂′R₃′ (where R₁′, R₂′ or R₃′=alkyl or

[0098] In each of the disclosed embodiments, C₁-C₄ alkyl can be selectedfrom the group consisting of methyl, ethyl, normal-propyl, iso-propyl,normal-butyl, iso-butyl, sec-butyl, and tert-butyl; and said aryl can beselected from the group consisting of phenyl, substituted phenyl,naphthyl, and substituted naphthyl groups. The epoxidation reactions canbe carried out in a homoogeneous solvent system selected from the groupconsisting of dimethoxymethane-acetonitrile-water, acetonitrile-water,acetone-water, dioxane-water, dimethoxyethane-water, andtetrahydrofuran-water, and mixtures thereof. Alternatively, theepoxidation reactions can be carried out in a biphasic solvent systemselected from the group consisting of dichloromethane-water,chloroform-water, benzene-water, toluene-water, dimethoxymethane-water,or diethylether-water and mixtures thereof.

[0099] Suitable oxidation agents for the epoxidation reactions of theinstant invention include potassium peroxomonosulfate, sodiumhypochlorite, sodium perborate, hydrogen peroxide, and peracids.

[0100] The epoxidation reactions of the instant invention catalyzed by aketone can be carried out at a temperature within the range from about−10° C. to about 40° C. Direct dioxirane epoxidation reactions of theinstant invention can be carried out at a temperature within the rangeof from about −40° C. to about 40° C. Some epoxidation reactions of theinstant invention can be carried out at about room temperature.

[0101] The epoxidation reactions of the instant invention can be carriedout at a pH within the range from about 7.0 to about 12.0. Some suchepoxidation reactions can be carried out at a pH within the range fromabout 7.0 to about 7.5. The pH can be controlled by using a pH-statmachine such as is known in the art, or a buffer. Suitable buffersinclude solutions of sodium bicarbonate, sodium carbonate, sodiumborate, sodium hydrogenphosphate, sodium dihydrogenphosphate, sodiumhydroxide, potassium hydrogenphosphate, potassium dihydrogenphosphate,potassium bicarbonate, potassium carbonate and potassium hydroxide.

[0102] We first examined four efficient ketone catalysts 1-4 for the insitu epoxidation of cholesterol 5 (FIG. 2). A modified homogeneoussolvent system (a mixture of DMM/CH₃CN/H₂O in a 3:1:2 ratio) was used toincrease the solubility of steroid substrates (FIG. 3). The results aresummarized in Table 1. The ratio of β/α-epoxides was determined byintegration of C(6) proton signals in the ¹H NMR spectra of the cruderesidues (δ3.00-3.15 ppm for β-epoxides and 67 2.75-2.95 ppm forα-epoxides). While ketones 1-3 exhibited poor β-selectivities (β/αepoxide ratio ca. 1:1; entries 1-3), ketone 4 with the most bulkyα-substituent gave the best β-selectivity (β/α epoxide ratio 15.1:1;entry 4). A variety of 3β-substituted Δ⁵-steroids 6-10 (FIG. 2) werethen subjected to the in situ epoxidation conditions with 20-30 mol % ofketone 4. The results revealed that ketone 4 generally gave highβ-selectivities (β/α epoxide ratio >8.5:1) and high yields (entries4-10). It is interesting to note that Δ⁵-steroids with a free C3-OHgroup were directly converted to their 5β,6β-epoxides with highselectivity and yields (entries 4, 5, and 7-9). (Note: The free 3-OHgroup of Δ⁵-unsaturated steroids is not compatible with some metal-basedoxidants in the epoxidation reactions.) Meanwhile, a wide range offunctional groups such as hydroxyl, methoxyl, methoxymethyl ether, andcarbonyl group were well tolerated under the mild and neutral reactionconditions (room temperature, pH 7-7.5).

[0103] Epoxidation reactions of 3α-substituted Δ⁵-steroids 11-20 werealso carried out with ketone catalysts 1-4 (FIG. 2) and the ketonecatalyst acetone. For epicholesterol 11 with a 3α-OH group, theepoxidation reactions catalyzed by ketones 1 and 4 gave much higher,selectivities than those by ketones 2 and 3 (Table 2; entries 1-4) andacetone (see Table 3). This is because ketones 1 and 4 have largerα-substituents. For substrates with 3α-substituents larger than the OHgroup (12-20), the in situ epoxidation catalyzed by ketones 1-4 andacetone produced almost single 5β,6β-isomers (Table 2, β/α ratio>49:1,entries 5-24; Table 3). Substrates with 3-ketal group are of particularinterest since highly α-selective epoxidation with trifluoroperaceticacid has been reported for this class of Δ⁵-steroids. Epoxidation ofsubstrates 13-20 with mCPBA gave ca. 1:1 ratio of β/α-epoxides. Theepoxidation reactions catalyzed by ketone 2 were highly efficient asonly 5 mol % of the catalyst was needed even on a preparative scale. Forexample, a multi-gram scale (10 mmol) epoxidation of substrate 18catalyzed by ketone 2 (5 mol %) provided almost a single β-epoxide(β/α-epoxide ratio>99:1) in 88% yield. These results clearly demonstratethe power of ketone-catalyzed epoxidation method.

[0104] In summary, we have developed a general, efficient andenvironmentally friendly method for highly β-selective epoxidation ofΔ⁵-unsaturated steroids. With this method in hand, a library of5β,6β-epoxides and their derivatives can be readily constructed and thenscreened for potential ligands that bind to orphan nuclear receptors.This is crucial for elucidating the biological functions of thosereceptors as well as for drug discovery.

General Experimental

[0105] The ¹H and ¹³C NMR spectra (FIGS. 4-70) were recorded indeuteriochloroform (CDCl₃) with tetramethylsilane (TMS) as internalstandard at ambient temperature on a Bruker Avance DPX 300 or 500Fourier Transform Spectrometer. Infrared absorption spectra wererecorded as a solution in CH₂Cl₂ on a Bio-Rad FTS 165 Fourier TransformSpectrophotometer. Mass spectra were recorded with a Finningan MAT 95mass spectrometer for both low resolution and high resolution massspectra.

[0106] Substrates 5, 6, 8, 9, ketone 1, tetrahydrothiopyran-4-one(precursor of ketone 2), and Oxone® were purchased from Aldrich or AcrosChemical Co. and used without further purification. Substrates 7, 10,11, 12, 13-20, and ketones 3, 4 were prepared according to theliterature procedures.

Typical Procedure for in situ Epoxidation Reactions

[0107] Epoxidation of Cholesterol 5 Catalyzed by Ketone 4 (Table 1,Entry 4). To a solution of cholesterol 5 (116 mg 0.3 mmol) and ketone 4(41 mg, 0.09 mmol) in dimethoxymethane (DMM, 9 mL) and acetonitrile(CH₃CN, 3 mL) at room temperature was added an aqueous Na₂·EDTA solution(6 mL, 4×10⁻⁴ M). To this mixture was added in portions a mixture ofOxone® (922 mg, 1.5 mmol) and sodium bicarbonate (391 mg, 4.65 mmol)over the reaction period. The reaction mixture was poured into water,and extracted with ethyl acetate three times. The combined organiclayers were dried over anhydrous MgSO₄ and filtered through a pad ofsilica gel. The ratio of α/β-epoxides was determined by ¹H NMR analysisof the crude residue which was obtained after removal of the solventunder reduced pressure. Pure products were obtained after flash columnchromatography on silica gel (99 mg, 82% yield).

[0108] Epoxidation of Substrate 13 Catalyzed by Ketone 2 (Table 2, Entry8). To a solution of substrate 13 (112 mg 0.3 mmol) andtetrahydrothiopyran-4-one (1.7 mg, 0.015 mmol) in dimethoxymethane (DMM,9 mL) and acetonitrile (CH₃CN, 3 mL) at room temperature was added anaqueous Na₂. EDTA solution (6 mL, 4×10⁻⁴ M). To this mixture was addedin portions a mixture of Oxone® (922 mg, 1.5 mmol) and sodiumbicarbonate (391 mg, 4.65 mmol) over a period of 1.5 h. The reaction wascomplete in 2 h as shown by TLC. The reaction mixture was poured intowater, and extracted with ethyl acetate three times. The combinedorganic layers were dried over anhydrous MgSO₄ and filtered through apad of silica gel. The ratio of α/β-epoxides was determined by ¹H NMRanalysis of the crude residue which was obtained after removal of thesolvent under reduced pressure. Pure epoxide was obtained after flashcolumn chromatography on silica gel (110 mg, 94% yield).

Procedure for Preparative Scale Epoxidation Reactions

[0109] Epoxidation of Substrate 9 Catalyzed by Ketone 4 (Table 1, Entry9). To a solution of substrate 9 (3.17 g 10 mmol) and ketone 4 (1.37 g,3 mmol) in dimethoxymethane (DMM, 300 mL) and acetonitrile (CH₃CN, 100mL) at room temperature was added an aqueous Na₂.EDTA solution (200 mL,4×10⁻⁴ M). To this mixture was added in portions a mixture of Oxone®(30.74 g, 50 mmol) and sodium bicarbonate (13.02 g, 155 mmol) over aperiod of 8 h. The reaction was complete in 10 h as shown by TLC. Thereaction mixture was poured into water, and extracted with ethyl acetatethree times. The combined organic layers were dried over anhydrous MgSO₄and filtered through a pad of silica gel. The ratio of α/β-epoxides wasdetermined by ¹H NMR analysis of the crude residue which was obtainedafter removal of the solvent under reduced pressure. Pure products wereobtained after flash column chromatography on silica gel (2.86 g, 86%yield).

[0110] Epoxidation of Substrate 18 Catalyzed by Ketone 2 (Table 2, Entry19). To a solution of substrate 18 (4.03 g 10 mmol) andtetrahydrothiopyran-4-one (58 mg, 0.5 mmol) in dimethoxymethane (DMM,300 mL) and acetonitrile (CH₃CN, 100 mL) at room temperature was addedan aqueous Na₂.EDTA solution (200 mL, 4×10⁻⁴ M). To this mixture wasadded in portions a mixture of Oxone® (30.74 mg, 50 mmol) and sodiumbicarbonate (13.02 g, 155 mmol) over a period of 4 h. The reaction wascomplete in 5 h as shown by TLC. The reaction mixture was poured intowater, and extracted with ethyl acetate three times. The combinedorganic layers were dried over anhydrous MgSO₄ and filtered through apad of silica gel. The ratio of α/β-epoxides was determined by ¹H NMRanalysis of the crude residue which was obtained after removal of thesolvent under reduced pressure. Pure epoxide was obtained after flashcolumn chromatography on silica gel (3.68 g, 88% yield).

General Procedure for Epoxidation of Δ⁵-Unsaturated Steroids with mCPBA

[0111] Sodium bicarbonate (0.4 mmol) and mCPBA (0.2 mmol) were added toa solution of substrate (0.1 mmol) in CH₂Cl₂ (3 ml). The resultingmixture was stirred at room temperature for 2 h and quenched with asolution of saturated aqueous Na₂S₂O₃. The reaction mixture was dilutedwith ethyl acetate and washed with a solution of saturated aqueousNaHCO₃ and brine. The organic layer was dried over anhydrous MgSO₄ andfiltered through a pad of silica gel. The product analysis was performedas above.

Characterization Data for Epoxides

[0112]

[0113] 5a and 5b (as a mixture of 1:15.1 ratio; Table 1, Entry 4):

[0114]¹H NMR (300 MHz, CDCl₃) δ3.94-3.86 (m, 1/16.1×1H, 3α-H), 3.74-3.64(m, 15.1/16.1×1H, 3α-H), 3.06 (d, J=2.2 Hz, 15.1/16.1×1H, 6α-H), 2.90(d, J=4.3 Hz, 1/16.1×1H, 6β-H), 1.06 (s, 1/16.1×3H, 19-CH₃), 0.99 (s,15.1/16.1×3H, 19-CH₃), 0.89 (d, J=6.6 Hz, 15.1/16.1×3H, 21-CH₃), 0.86(d, J=6.6 Hz, 15.1/16.1×6H, 26-CH₃ and 27CH₃), 0.64 (s, 15.1/16.1×3H,18-CH₃), 0.61 (s, 1/16.1×3H, 18-CH₃); ¹³C NMR of 5b (75.5 MHz, CDCl₃)δ69.32, 63.76, 63.04, 56.21, 56.20, 51.32, 42.27, 42.18, 39.82, 39.48,37.22, 36.12, 35.71, 34.84, 32.59, 30.97, 29.76, 28.14, 27.99, 24.18,23.80, 22.81, 22.55, 21.98, 18.66, 17.05, 11.75.

[0115] 6a and 6b (as a mixture of 1:10.4 ratio; Table 1, Entry 5):

[0116]¹H NMR (300 MHz, CDCl₃) δ3.95-3.85 (m, 1/11.4×1H, 3α-H), 3.76-3.65(m, 10.4/11.4×1H, 3α-H), 3.13 (d, J=2.5 Hz, 10.4/11.4×1H, 6α-H), 2.95(d, J=4.3 Hz, 1/11.4×1H, 6β-H), 1.09 (s, 1/11.4×3H, 19-CH₃), 1.03 (s,10.4/11.4×3H, 19-CH₃), 0.85 (s, 10.4/11.4×3H, 18-CH₃) 0.82 (s,1/11.4×3H, 18-CH₃); ¹³C NMR of 6b (75.5 MHz, CDCl₃) δ220.97, 69.2163.32, 63.05, 51.47, 51.18, 47.49, 42.05, 37.24, 35.74, 35.10, 31.51,31.46, 30.93, 29.47, 21.73, 21.28, 17.08, 13.47.

[0117] 7a and 7b (as a mixture of 1:9; Table 1, Entry 6):

[0118]¹H NMR (500 MHz, CDCl₃) δ=3.45-3.38 (m, 1/10×1H, 3α-H), 3.34 (s,3H, OCH₃) 3.28-3.22 (m, 9/10×1H, 3α-H), 3.11 (d, J=2.4 Hz, 9/10×1H,6α-H), 2.95 (d, J=4.4 Hz, 1/10×1H, 6β-H), 1.18 (s, 9/10×3H, 19-CH₃),1.17 (s, 1/10×3H, 19-CH₃), 1.02 (s, 9/10×6H, 20-CH₃ and 21-CH₃), 0.87(s, 9/10×3H, 18-CH₃), 0.85 (s, 1/10×3H, 18-CH₃); ¹³C NMR of 9 b (75.5MHz, CDCl₃) δ=225.00, 77.70, 63.15, 63.04, 55.71, 51.37, 48.52, 48.01,45.15, 38.63, 37.82, 36.75, 35.54, 32.30, 31.66, 28.93, 27.27, 27.02,25.95, 21.08, 17.13, 14.08; IR (CH₂Cl₂) 1730 cm⁻¹; LRMS (EI, 20 eV) m/z346 (100), 314 (15), 123 (31), 108 (22); HRMS (EI, 20 eV) calcd forC₂₂H₃₄O₃ (M⁺): 346.2508, found: 346.2508; Anal. Calcd for C₂₂H₃₄O₃: C,76.26; H, 9.89; Found: C, 76.14; H, 9.90.

[0119] 8a and 8b (as a mixture of 1:8.8 ratio; Table 1, Entry 7):

[0120]¹H NMR (300 MHz, CDCl₃) δ3.95-3.84 (m, 1/9.8×1H, 3α-H), 3.74-3.64(m, 8.8/9.8×1H, 3α-H), 3.60 (t, J=8.5 Hz, 1H, 17α-H), 3.07 (d, J=2.4 Hz,8.8/9.8×1H, 6α-H), 2.91 (d, J=4.4 Hz, 1/9.8×1H, 6β-H), 1.07 (s,1/9.8×3H, 19-CH₃), 1.01 (s, 8.8/9.8×3H, 19-Ch₃), 0.72 (s, 8.8/9.8×3H,18-CH₃), 0.69 (s, 1/9.8×3H, 18-CH₃); ¹³C NMR of 8 b (75.5 MHz, CDCl₃)δ81.81, 69.31, 63.51, 63.01, 51.48, 50.74, 42.67, 42.15, 37.25, 36.62,34.99, 32.19, 30.97, 30.42, 29.81, 23.31, 21.60, 17.12, 10.86.

[0121] 9a and 9b (as a mixture of 1:11.6; Table 1, Entry 8):

[0122]¹H NMR (300 MHz, CDCl₃) δ3.94-3.87 (m, 1/12.6×1H, 3α-H), 3.75-3.65(m, 11.6/12.6×1H, 3α-H), 3.08 (d, J=2.3 Hz, 11.6/12.6×1H, 6α-H), 2.92(d, J=4.4 Hz, 1/12.6×1H, 6β-H), 2.11 (s, 11.6/12.6×3H, 21-CH₃) 1.06 (s,1/12.6×3H, 19-CH₃), 1.00 (s, 11.6/12.6×3H, 19-CH₃), 0.59 (s,11.6/12.6×3H, 18-CH₃) 0.56 (s, 1/12.6×3H, 18-CH₃); ¹³C NMR of 9b (75.5MHz, CDCl₃) δ209.48, 69.29, 63.67, 63.50, 62.89, 56.33, 51.19, 43.89,42.12, 38.84, 4.92, 32.51, 31.46, 30.97, 29.76, 24.36, 22.77, 21.96,17.07, 13.11.

[0123] 10a and 10b (as a mixture of: 18.5; Table 1, Entry 10):

[0124]¹H NMR (300 MHz, CDCl₃) δ4.73-4.64 (m, 2H, OCH₂O), 3.83-3.74 (m,1/9.5×1H, 3α-H), 3.65-3.55 (m, 8.5/9.5×1H, 3α-H), 3.36 (s, 8.5/9.5×3H,OCH₃), 3.35 (s, 1/9.5×3H, OCH₃), 3.08 (d, J=2.3 Hz, 8.5/9.5×1H, 6α-H),2.91 (d, J=4.3 Hz, 1/9.5×1H, 6α-H), 2.11 (s, 8.5/9.5×3H, 21-CH₃), 1.06(s, 1/9.5×3H, 19-CH₃), 1.00 (s, 8.5/9.5×3H, 19-CH₃), 0.60 (s,8.5/9.5×3H, 18-CH₃), 0.56 (s, 1/9.5×3H, 18-CH₃); ¹³C NMR of 11 b (75.5MHz, CDCl₃) δ209.35, 94.67, 74.18, 63.67, 63.44, 62.82, 56.33, 55.26,51.08, 43.88, 39.43, 38.84, 37.07, 35.16, 32.48, 31.45, 29.74, 28.13,24.35, 22.77, 21.94, 17.07, 13.11; IR (CH₂Cl₂) 1700 cm⁻¹; EIMS (20 eV)m/z 376 (100), 314 (90), 133 (36), 95 (33); HRMS (EI, 20 eV) calcd forC₂₃H₃₆O₄ (M⁺): 376.2614, found: 376.2617; Anal. Calcd for C₂₃H₃₆O₄: C,73.37; H, 9.64; Found: C, 73.11; H, 9.68.

[0125] 11b:

[0126]¹H NMR (300 MHz, CDCl₃) δ4.19 (br s, 1H, 3α-H), 3.07 (d, J=2.0 Hz,1H, 6α-H), 0.97 (s, 3H, 19-CH₃), 0.89 (d, J=6.6 Hz, 3H, 21-CH₃), 0.86(d, J=6.6 Hz, 6H, 26-CH₃ and 27-CH₃), 0.64 (s, 3H, 18-CH₃); ¹³C NMR(75.5 MHz, CDCl₃) δ67.03, 63.70, 61.97, 56.31, 56.20, 50.38, 42.31,39.87, 39.86, 39.49, 36.14, 35.74, 35.53, 33.19, 32.37, 29.82, 28.40,28.17, 27.99, 24.18, 23.83, 22.81, 22.55, 21.69, 18.67, 17.00, 11.78.

[0127] 11a:

[0128]¹H NMR (300 MHz, CDCl₃) δ4.10-4.07 (m, 1H, 3β-H), 2.87 (d, J=4.5Hz, 1H, 6β-H), 1.04 (s, 3H, 19-CH₃), 0.89 (d, J=6.6 Hz, 3H, 21-CH₃),0.86 (d, J=6.6 Hz, 6H, 26-CH₃ and 27-CH₃), 0.61 (s, 3H, 18-CH₃); ¹³C NMR(75.5 MHz, CDCl₃) δ67.98, 65.43, 57.79, 56.86, 55.84, 42.66, 42.32,39.49, 39.36, 36.41, 36.13, 35.76, 35.52, 29.62, 28.92, 28.63, 28.59,28.07, 28.00, 24.02, 23.84, 22.82, 22.56, 20.28, 18.64, 15.34, 11.86.

[0129] 12b:

[0130]¹H NMR (300 MHz, CDCl₃) δ5.12-5.10 (m, 1H, 3β-H), 3.00 (d, J=2.0Hz, 1H, 6α-H), 2.04 (s, 3H, CH₃COO), 0.99 (s, 3H, 19-CH₃), 0.89 (d,J=6.6 Hz, 3H, 21-CH₃), 0.86 (d, J=6.6 Hz, 6H, 26-CH₃ and 27-CH₃), 0.65(s, 3H, 18-CH₃); ¹³C NMR (75.5 MHz, CDCl₃) δ170.52, 70.50, 63.28, 61.69,56.33, 56.27, 50.20, 42.34, 39.86, 39.49, 36.63, 36.15, 35.76, 35.43,33.78, 32.43, 29.81, 28.19, 28.01, 25.47, 24.19, 23.85, 22.82, 22.56,21.71, 21.34, 18.68, 17.13, 11.78.

[0131] 13b:

[0132]¹H NMR (300 MHz, CDCl₃) δ3.97-3.79 (m, 8H, OCH₂CH₂O), 3.06 (d,J=2.1 Hz, 1H, 6α-H), 1.00 (s, 3H, 19-CH₃), 0.82 (s, 3H, 18-CH₃); ³C NMR(75.5 MHz, CDCl₃) δ119.12, 109.19, 64.97, 64.33, 64.12, 63.94, 62.90,62.76, 49.81, 49.53, 45.50, 41.29, 35.43, 34.97, 33.91, 31.44, 30.64,30.38, 29.78, 22.44, 21.20, 16.94, 13.96.

[0133] 14b:

[0134]¹H NMR (300 MHz, CDCl₃) δ3.97-3.85 (m, 4H, OCH₂CH₂O), 3.05 (d,J=1.9 Hz, 1H, 6α-H), 0.99 (s, 3H, 19-CH₃), 0.89 (d, J=6.7 Hz, 3H,21-CH₃), 0.86 (d, J=6.6 Hz, 6H, 26-CH₃ and 27-CH₃), 0.64 (s, 3H,18-CH₃); ¹³C NMR (75.5 MHz, CDCl₃) δ109.45, 64.27, 64.09, 63.29, 56.24,56.15, 49.85, 42.28, 41.46, 39.81, 39.47, 36.11, 35.71, 35.61, 35.01,32.27, 30.82, 29.67, 28.15, 27.98, 24.16, 23.79, 22.81, 22.54, 21.89,18.66, 17.06, 11.75.

[0135] 15b:

[0136]¹H NMR (300 MHz, CDCl₃) δ3.97-3.87 (m, 4H, OCH₂CH₂O), 3.60 (t,J=8.5 Hz, 1H, 17α-H), 3.07 (d, J=2.2 Hz, 1H, 6α-H), 1.01 (s, 3H,19-CH₃), 0.72 (s, 3H, 18-CH₃); ¹³C NMR (75.5 MHz, CDCl₃) δ109.41, 81.78,64.31, 64.14, 63.14, 63.05, 50.79, 50.07, 42.70, 41.45, 36.63, 35.66,35.17, 31.87, 30.81, 30.45, 29.73, 23.31, 21.53, 17.14, 10.88.

[0137] 16b:

[0138]¹H NMR (300 MHz, CDCl₃) δ4.56 (dd, J=9.0, 7.9 Hz, 1H, 17α-H),3.95-3.89 (m, 4H, OCH₂CH₂O), 3.07 (d, J=2.2 Hz, 1H, 6α-H), 2.03 (s, 3H,CH₃COO), 1.00 (s, 3H, 19-CH₃), 0.77 (s, 3H, 18-CH₃); ¹³C NMR (75.5 MHz,CDCl₃) δ171.20, 109.34, 82.64, 64.30, 64.14, 63.09, 63.00 50.53, 49.94,42.33, 41.45, 36.79, 35.68, 35.14, 31.85, 30.78, 29.52, 27.43, 23.44,21.39, 21.15, 17.11, 11.84.

[0139] 17b:

[0140]¹H NMR (300 MHz, CDCl₃) δ3.95-3.90 (m, 4H, OCH₂CH₂O), 3.07 (d,J=2.1 Hz, 1H, 6α-H), 2.11 (s, 3H, 21-CH₃), 1.00 (s, 3H, 19-CH₃), 0.60(s, 3H, 18-CH₃); ¹³C NMR (75.5 MHz, CDCl₃) δ209.41, 109.37, 64.33,64.16, 63.66, 63.15, 62.95, 56.40, 49.84, 43.92, 41.42, 38.85, 35.71,35.10, 32.21, 31.47, 30.82, 29.70, 24.36, 22.78, 21.90, 17.09, 13.12.

[0141]18 b:

[0142]¹H NMR (300 MHz, CDCl₃) δ4.04-3.81 (m, 8H, OCH₂CH₂O), 3.06 (d,J=1.8 Hz, 1H, 6α-H),1.28 (s, 3H, 21-CH₃), 1.00 (s, 3H, 19-CH₃), 0.74 (s,3H, 18-CH₃); ¹³-C NMR (75.5 MHz, CDCl₃) δ111.85, 109.44, 65.16, 64.29,64.12, 63.26, 63.19, 63.00, 58.21, 56.12, 49.87, 41.75, 9.44, 35.62,35.06, 32.18, 30.82, 29.22, 24.54, 23.70, 22.90, 21.67, 17.10, 12.76.

[0143] 19b:

[0144]¹H NMR (300 MHz, CDCl₃) δ4.03-3.81 (m, 9H, 11β-H and OCH₂CH₂O),3.08 (d, J=2.6 Hz1H, 6α-H), 1.28 (s, 3H, 21-CH₃), 1.20 (s, 3H, 19-CH₃),0.76 (s, 3H, 18-CH₃); ¹³C NMR (75.5 MHz, CDCl₃) δ111.47, 109.02, 68.68,64.98, 64.17, 64.04, 63.35, 63.10, 62.90, 57.80, 57.01, 55.22, 50.60,42.45, 41.81, 37.41, 35.87, 31.40, 30.57, 27.91, 24.40, 23.42, 22.97,15.55, 13.86.

[0145] 20b:

[0146]¹H NMR (300 MHz, CDCl₃) δ5.07 (td, J=10.9, 4.8 Hz, 1H, 11β-H),3.99-3.83 (m, 8H, OCH₂CH₂O), 3.08 (d, J=2.7 Hz, 1H, 6α-H), 2.01 (s, 3H,CH₃COO), 1.24 (s, 3H, 21-CH₃), 1.02 (s, 3H, 19-CH₃), 0.82 (s, 3H,18-CH₃); ¹³C NMR (75.5 MHz, CDCl₃) δ169.76, 111.42, 108.87, 72.38,64.96, 64.28, 64.17, 63.16, 63.02, 62.69, 57.73, 55.09, 53.57, 45.36,42.23, 41.86, 37.02, 35.85, 31.56, 30.70, 28.09, 24.46, 23.52, 23.19,21.87, 16.06, 13.58.

Determination of the Ratio of β/α-epoxides

[0147] The ratio of β/α-epoxides was determined by integration of theC(6) proton signals in the ¹H NMR spetra (300 or 500 MHz) of cruderesidues (δ3.00-3.15 ppm for β-epoxides and δ 2.75-2.95 ppm forα-epoxides). The authentic samples of 5a/5b-20a/20b were prepared byepoxidation of substrates 5-20 with mCPBA according to the literatureprocedure.

EXAMPLES Example 1 5β,6β-Epoxycholestan-3β-ol (Catalyzed by Ketone 4)

[0148] To a solution of cholesterol (116 mg 0.3 mmol) and ketone 4 (41mg, 0.09 mmol) in dimethoxymethane (9 mL) and acetonitrile (3 mL) atroom temperature was added an aqueous Na₂.EDTA solution (6 mL, 4×10⁻⁴M). To this mixture was added in portions a mixture of Oxone® (922 mg,1.5 mmol) and sodium bicarbonate (391 mg, 4.65 mmol) over the reactionperiod. The reaction mixture was poured into water, and extracted withethyl acetate three times. The combined organic layers were dried overanhydrous MgSO₄ and filtered through a pad of silica gel. ¹H NMRanalysis of the product showed that the ratio of β/α-epoxides was15.1:1. Pure products were obtained after flash column chromatography onsilica gel (99 mg, 82% yield).

Example 2 5β,6β-Epoxyandrostene-3,17-dione 3,17-diethylene Ketal(Catalyzed by Ketone 1)

[0149] To a solution of 5-androstene-3,17-dione 3,17-diethylene ketal(112 mg 0.3 mmol) in dimethoxymethane (9 mL) and acetonitrile (3 mL) wasadded an aqueous Na₂·EDTA solution (6 mL, 4×10⁻⁴ M), the resultingsolution was cooled to 0-1° C., followed by addition of1,1,1-trifluoroacetone (0.54 mL, 6 mmol). To this solution was added inportions a mixture of Oxone® (922 mg, 1.5 mmol) and sodium bicarbonate(391 mg, 4.65 mmol) over a period of 0.5 h. The reaction was complete in1 h as shown by TLC. The reaction mixture was poured into water, andextracted with ethyl acetate three times. The combined organic layerswere dried over anhydrous MgSO₄ and filtered through a pad of silicagel. ¹H NMR analysis of the crude residue showed that the ratio ofβ/α-epoxides was >99:1. 5β,6β-Epoxyandrostene-3,17-dione 3,17-diethyleneketal was obtained after flash column chromatography on silica gel (101mg, 86% yield).

Example 3 5β,6β-Epoxyandrostene-3,17-dione 3,17-diethylene Ketal(Catalyzed by Ketone 2)

[0150] To a solution of 5-androstene-3,17-dione 3,17-diethylene ketal(112 mg 0.3 mmol) and tetrahydrothiopyran-4-one (1.7 mg, 0.015 mmol) indimethoxymethane (9 mL) and acetonitrile (3 mL) at room temperature wasadded an aqueous Na₂.EDTA solution (6 mL, 4×10⁻⁴ M). To this mixture wasadded in portions a mixture of Oxone® (922 mg, 1.5 mmol) and sodiumbicarbonate (391 mg, 4.65 mmol) over a period of 1.5 h. The reaction wascomplete in 2 h as shown by TLC. The reaction mixture was poured intowater, and extracted with ethyl acetate three times. The combinedorganic layers were dried over anhydrous MgSO₄ and filtered through apad of silica gel. ¹H NMR analysis of the crude residue showed that theratio of β/α-epoxides was 96:1. 5β,6β-Epoxyandrostene-3,17-dione3,17-diethylene ketal was obtained after flash column chromatography onsilica gel (110 mg, 94% yield).

Example 4 5β,6β-Epoxyandrostene-3,17-dione 3,17-diethylene Ketal(Catalyzed by Ketone 3)

[0151] To a solution of 5-androstene-3,17-dione 3,17-diethylene ketal(112 mg 0.3 mmol) and ketone 3 (9 mg, 0.03 mmol) in dimethoxymethane (9mL) and acetonitrile (3 mL) at room temperature was added an aqueousNa₂·EDTA solution (6 mL, 4×10⁻⁴ M). To this mixture was added inportions a mixture of Oxone® (922 mg, 1.5 mmol) and sodium bicarbonate(391 mg, 4.65 mmol) over a period of 1 h. The reaction was complete in1.5 h as shown by TLC. The reaction mixture was poured into water, andextracted with ethyl acetate three times. The combined organic layerswere dried over anhydrous MgSO₄ and filtered through a pad of silicagel. ¹H NMR analysis of the crude residue showed that the ratio ofβ/α-epoxides was 49:1. 5β,6β-Epoxyandrostene-3,17-dione 3,17-diethyleneketal was obtained after flash column chromatography on silica gel (109mg, 93% yield).

Example 5 5β,6β-Epoxyandrostene-3,17-dione 3,17-diethylene Ketal(Catalyzed by Acetone)

[0152] To a solution of 5-androstene-3,17-dione 3,17-diethylene ketal(112 mg 0.3 mmol) and acetone (522 mg, 9 mmol) in dimethoxymethane (9mL) and acetonitrile (3 mL) at room temperature was added an aqueousNa₂·EDTA solution (6 mL, 4×10⁻⁴ M). To this mixture was added inportions a mixture of Oxone® (922 mg, 1.5 mmol) and sodium bicarbonate(391 mg, 4.65 mmol) over a period of 4 h. The reaction was complete in 5h as shown by TLC. The reaction mixture was poured into water, andextracted with ethyl acetate three times. The combined organic layerswere dried over anhydrous MgSO₄ and filtered through a pad of silicagel. ¹H NMR analysis of the crude residue showed that the ratio ofβ/α-epoxides was >99:1. 5β,6β-Epoxyandrostene-3,17-dione 3,17-diethyleneketal was obtained after flash column chromatography on silica gel (110mg, 94% yield).

Example 6 5β,6β-Epoxyandrostene-3,17-dione 3,17-diethylene Ketal(Acetone as Catalyst and Cosolvent)

[0153] To a solution of 5-androstene-3,17-dione 3,17-diethylene ketal(112 mg 0.3 mmol) in actone (15 mL) at room temperature was added anaqueous Na₂.EDTA solution (5 mL, 4×10⁻⁴ M). To this mixture was added inportions a mixture of Oxone® (922 mg, 1.5 mmol) and sodium bicarbonate(391 mg, 4.65 mmol) over a period of 1.5 h. The reaction was complete in2 h as shown by TLC. The reaction mixture was poured into water, andextracted with ethyl acetate three times. The combined organic layerswere dried over anhydrous MgSO₄ and filtered through a pad of silicagel. ¹H NMR analysis of the crude residue showed that the ratio ofβ/α-epoxides was >99:1. 5β,6β-Epoxyandrostene-3,17-dione 3,17-diethyleneketal was obtained after flash column chromatography on silica gel (105mg, 90% yield).

Example 7 5β,6β-Epoxy-3β-Hydroxypregnan-20-one (Catalyzed by Ketone 4)

[0154] To a solution of pregnenolone (3.17 g 10 mmol) and ketone 4 (1.37g, 3 mmol) in dimethoxymethane (300 mL) and acetonitrile (100 mL) atroom temperature was added an aqueous Na₂.EDTA solution (200 mL, 4×10⁻⁴M). To this mixture was added in portions a mixture of Oxone® (30.74 g,50 mmol) and sodium bicarbonate (13.02 g, 155 mmol) over a period of 8h. The reaction was complete in 10 h as shown by TLC. The reactionmixture was poured into water, and extracted with ethyl acetate threetimes. The combined organic layers were dried over anhydrous MgSO₄ andfiltered through a pad of silica gel. ¹H NMR analysis of the productshowed that he ratio of β/α-epoxides was 16.0:1. Pure products wereobtained after flash column chromatography on silica gel (2.86 g, 86%yield).

Example 8 5β,6β-Epoxy-11α-hydroxypregnene-3,20-dione 3-diethylene Ketal(Catalyzed by Ketone 2)

[0155] To a solution of 5-pregnene-3,20-dione 3,20-diethylene ketal(4.03 g 10 mmol) and tetrahydrothiopyran-4-one (58 mg, 0.5 mmol) indimethoxymethane (300 mL) and acetonitrile (100 mL) at room temperaturewas added an aqueous Na₂·EDTA solution (200 mL, 4×10⁻⁴ M). To thismixture was added in portions a mixture of Oxone® (30.74 mg, 50 mmol)and sodium bicarbonate (13.02 g, 155 mmol) over a period of 4 h. Thereaction was complete in 5 h as shown by TLC. The reaction mixture waspoured into water, and extracted with ethyl acetate three times. Thecombined organic layers were dried over anhydrous MgSO₄ and filteredthrough a pad of silica gel. ¹H NMR analysis of the crude residue showedthat the ratio of β/α-epoxides was >99:1. 5β,6β-Epoxypregnene-3,20-dione3,20-diethylene ketal was obtained after flash column chromatography onsilica gel (3.68 g, 88% yield).

Example 9 5β,6β-Epoxy-3β-hydroxyandrostan-17-one (Catalyzed by Ketone 4)

[0156] Following the procedure of Example 1 above,dehydroisoandrosterone was epoxidized to5β,6β-epoxy-3β-hydroxyandrostan-17-one.

Example 10 5β,6β-Epoxy-16,16-dimethyl-3β-methoxyandrostan-17-one(Catalyzed by Ketone 4)

[0157] Following the procedure of Example 1 above,16,16-dimethyl-3β-methoxy-5-androsten-17-one was epoxidized to5β,6β-epoxy-16,16-dimethyl-3β-methoxyandrostan-17-one.

Example 11 5β,6β-Epoxyandrostane-3β,17β-diol (Catalyzed by Ketone 4)

[0158] Following the procedure of Example 1 above,5-androstene-3β,17β-diol was epoxidized to5β,6β-epoxyandrostane-3β,17β-diol.

Example 12 5β,6β-Epoxy-3β-methoxymethoxypregnan-20-one (Catalyzed byKetone 4)

[0159] Following the procedure of Example 1 above,3β-methoxymethoxy-5-pregnen-20-one was epoxidized to5β,6β-epoxy-3β-methoxymethoxypregnan-20-one.

Example 13 5β,6β-Epoxycholestan-3α-ol (Catalyzed by Ketone 4)

[0160] Following the procedure of Example 1 above, epicholesterol wasepoxidized to 5β,6β-epoxycholestan-3α-ol.

Example 14 5β,6β-Epoxy-3β-acetoxycholestane (Catalyzed by Ketone 2)

[0161] Following the procedure of Example 3 above,3α-acetoxycholest-5-ene was epoxidized to5β,6β-epoxy-3α-acetoxycholestane.

Example 15 5β,6β-Epoxy-3α-acetoxycholestane (Catalyzed by Ketone 4)

[0162] Following the procedure of Example 1 above,3α-acetoxycholest-5-ene was epoxidized to5β,6β-epoxy-3α-acetoxycholestane.

Example 16 5β,6β-Epoxycholestane-3-one 3-ethylene Ketal (Catalyzed byKetone 2)

[0163] Following the procedure of Example 3 above, 5-cholestene-3-one3-ethylene ketal was epoxidized to 5β,6β-epoxycholestane-3-one3-ethylene ketal.

Example 17 5β,6β-Epoxycholestane-3-one 3-ethylene Ketal (Catalyzed byKetone 4)

[0164] Following the procedure of Example 1 above, 5-cholestene-3-one3-ethylene ketal was epoxidized to 5β,6β-epoxycholestane-3-one3-ethylene ketal.

Example 18 5β,6β-Epoxy-17β-hydroxyandrostan-3-one 3-ethylene Ketal(Catalyzed by Ketone 2)

[0165] Following the procedure of Example 3 above,17β-hydroxyandrost-5-en-3-one 3-ethylene ketal was epoxidized to5β,6β-epoxy-17β-hydroxyandrostan-3-one 3-ethylene ketal.

Example 19 5β,6β-Epoxy-17β-hydroxyandrostan-3-one 3-ethylene Ketal(Catalyzed by Ketone 4)

[0166] Following the procedure of Example 1 above,17β-hydroxyandrost-5-en-3-one 3-ethylene ketal was epoxidized to5β,6β-epoxy-17β-hydroxyandrostan-3-one 3-ethylene ketal.

Example 20 5β,6β-Epoxy-17β-acetoxyandrostan-3-one 3-ethylene Ketal(Catalyzed by Ketone 2)

[0167] Following the procedure of Example 3 above,17β-acetoxyandrost-5-en-3-one 3-ethylene ketal was epoxidized to5β,6β-epoxy-17β-acetoxyandrostan-3-one 3-ethylene ketal.

Example 21 5β,6β-Epoxy-17β-acetoxyandrostan-3-one 3-ethylene Ketal(Catalyzed by Ketone 4)

[0168] Following the procedure of Example 1 above,17β-acetoxyandrost-5-en-3-one 3-ethylene ketal was epoxidized to5β,6β-epoxy-17β-acetoxyandrostan-3-one 3-ethylene ketal.

Example 22 5β,6β-Epoxypregnene-3,20-dione 3,20-diethylene Ketal(Catalyzed by Ketone 2)

[0169] Following the procedure of Example 3 above, 5-pregnene-3,20-dione3,20-diethylene ketal was epoxidized to 5β,6β-epoxypregnene-3,20-dione3,20-diethylene ketal.

Example 23 5β,6β-Epoxypregnene-3,20-dione 3,20-diethylene Ketal(Catalyzed by Ketone 4)

[0170] Following the procedure of Example 1 above, 5-pregnene-3,20-dione3,20-diethylene ketal was epoxidized to 5β,6β-epoxypregnene-3,20-dione3,20-diethylene ketal.

Example 24 5β,6β-Epoxypregnene-3,20-dione 3-diethylene Ketal (Catalyzedby Ketone 2)

[0171] Following the procedure of Example 3 above, 5-pregnene-3,20-dione3-ethylene ketal was epoxidized to 5β,6β-epoxypregnene-3,20-dione3-ethylene ketal.

Example 25 5β,6β-Epoxypregnene-3,20-dione 3-diethylene Ketal (Catalyzedby Ketone 4)

[0172] Following the procedure of Example 1 above, 5-pregnene-3,20-dione3-ethylene ketal was epoxidized to 5β,6β-epoxypregnene-3,20-dione3-ethylene ketal.

Example 26 5β,6β-Epoxy-11α-hydroxypregnene-3,20-dione 3-diethylene Ketal(Catalyzed by Ketone 2)

[0173] Following the procedure of Example 3 above,11α-hydroxy-5-pregnene-3,20-dione 3-ethylene ketal was epoxidized to5β,6β-epoxy-11α-hydroxypregnene-3,20-dione 3-diethylene ketal.

Example 27 5β,6β-Epoxy-11α-hydroxypregnene-3,20-dione 3-diethylene Ketal(Catalyzed by Ketone 4)

[0174] Following the procedure of Example 1 above,11α-hydroxy-5-pregnene-3,20-dione 3-ethylene ketal was epoxidzed to5β,6β-epoxy-11α-hydroxypregnene-3,20-dione 3-diethylene ketal.

Example 28 5β,6β-Epoxy-11α-acetoxypregnene-3,20-dione 3-diethylene Ketal(Catalyzed by Ketone 2)

[0175] Following the procedure of Example 3 above,11α-acetoxy-5-pregnene-3,20-dione 3-ethylene ketal was epoxidized to5β,6β-epoxy-11α-acetoxypregnene-3,20-dione 3-diethylene ketal.

Example 29 5β,6β-Epoxy-11α-acetoxypregnene-3,20-dione 3-diethylene Ketal(Catalyzed by Ketone 4)

[0176] Following the procedure of Example 1 above,11α-acetoxy-5-pregnene-3,20-dione 3-ethylene ketal was epoxidized to5β,6β-epoxy-11α-acetoxypregnene-3,20-dione 3-diethylene ketal.

Example 30 5β,6β-Epoxycholestan-3α-ol (catalyzed by Ketone 1)

[0177] Following the procedure of Example 2 above, epi-cholesterol wasepoxidized to 5β,6β-epoxycholestan-3α-ol.

Example 31 5β,6β-Epoxyandrostene-3,17-dione 3,17-diethylene Ketal(Catalyzed by Ketone 4)

[0178] Following the procedure of Example 1 above 5-cholestene-3-one3-ethylene ketal was epoxidized to 5β,6β-epoxyandrostene-3,17-dione3,17-diethylene ketal.

Example 32 5β,6β-Epoxycholestane-3-one 3-ethylene Ketal (Catalyzed byAcetone)

[0179] Following the procedure of Example 5 above, 5-cholestene-3-one3-ethylene ketal was epoxidized to 5β,6β-epoxycholestane-3-one3-ethylene ketal.

Example 33 5β,6β-Epoxy-17β-acetoxyandrostan-3-one 3-ethylene Ketal(Catalyzed by Acetone)

[0180] Following the procedure of Example 5 above,17β-acetoxyandrost-5-en-3-one 3-ethylene ketal was epoxidized to5β,6β-epoxy-17β-acetoxyandrostan-3-one 3-ethylene ketal.

Example 34 5β,6β-Epoxypregnene-3,20-dione 3-ethylene Ketal (Catalyzed byKetone 2)

[0181] Following the procedure of Example 3 above, 5-pregnene-3,20-dione3-ethylene ketal was epoxidized to 5β,6β-epoxypregnene-3,20-dione3-ethylene ketal.

Example 35 5β,6β-Epoxypregnene-3,20-dione 3-ethylene Ketal (Catalyzed byKetone 4)

[0182] Following the procedure of Example 1 above, 5-pregnene-3,20-dione3-ethylene ketal was epoxidized to 5β,6β-epoxypregnene-3,20-dione3-ethylene ketal.

Example 36 5β,6β-Epoxypregnene-3,20-dione 3,20-diethylene Ketal(Catalyzed by Acetone)

[0183] Following the procedure of Example 5 above, 5-pregnene-3,20-dione3,20-diethylene ketal was epoxidized to 5β,6β-epoxypregnene-3,20-dione3,20-diethylene ketal.

Example 37 5β,6,-Epoxy-11α-hyrdoxypregnene-3,20-dione 3,20-diethyleneKetal (Catalyzed by Acetone)

[0184] Following the procedure of Example 5 above,11α-hyrdoxy-5-pregnene-3,20-dione 3,20-diethylene ketal was epoxidizedto 5β,6β-epoxy-11α-hyrdoxypregnene-3,20-dione 3,20-diethylene ketal.

Example 38 5β,6β-Epoxy-11α-hyrdoxypregnene-3,20-dione 3,20-diethyleneKetal (Catalyzed by Ketone 2)

[0185] Following the procedure of Example 3 above,11α-hyrdoxy-5-pregnene-3,20-dione 3,20-diethylene ketal was epoxidizedto 5β,6β-epoxy-11α-hyrdoxypregnene-3,20-dione 3,20-diethylene ketal.

Example 39 5β,6β-Epoxy-11α-hyrdoxypregnene-3,20-dione 3,20-diethyleneKetal (Catalyzed by Ketone 4)

[0186] Following the procedure of Example 1 above,11α-hyrdoxy-5-pregnene-3,20-dione 3,20-diethylene ketal was epoxidizedto 5β,6β-epoxy-11α-hyrdoxypregnene-3,20-dione 3,20-diethylene ketal.

Example 40 5β,6β-Epoxy-11α-acetoxypregnene-3,20-dione 3,20-diethyleneKetal (Catalyzed by Ketone 2)

[0187] Following the procedure of Example 3 above,11α-acetoxy-5-pregnene-3,20-dione 3,20-diethylene ketal was epoxidizedto 5β,6β-epoxy-11α-acetoxypregnene-3,20-dione 3,20-diethylene ketal.

Example 41 5β,6β-Epoxy-11α-acetoxypregnene-3,20-dione 3,20-diethyleneKetal (Catalyzed by Ketone 4)

[0188] Following the procedure of Example 1 above,11α-acetoxy-5-pregnene-3,20-dione 3,20-diethylene ketal was epoxidizedto 5β,6β-epoxy-11α-acetoxypregnene-3,20-dione 3,20-diethylene ketal.

[0189] The invention has been described with reference to preferredembodiments. Those skilled in the art will perceive improvements,changes and modifications. Such improvements, changes and modificationsare intended to be within the scope of the claims. TABLE 1Stereoselective epoxidation of 3β-substituted Δ⁵-steroids by dioxiranesgenerated in situ.^(a) catalyst reaction ketone loading time yieldβ/α-epoxide entry catalyst substrate (equivalent) (h)^(b) (%)^(c)ratio^(d,e) 1 1^(f) 5 20 1.5 91 1/1.1 (1/4.0) 2 2 5 0.05 1.5 93 1.1/1 33 5 0.1 3 92 1/1.1 4 4 5 0.3 16 82 15.1/1 5 4 6 0.2 9 91 10.4/1 (1/3.9)6 4 7 0.2 20 88 9.0/1 (1/3.1) 7 4 8 0.2 16 85 8.8/1 (1/3.1) 8 4 9 0.2 993 11.6/1 (1/4.3) 9^(g) 4 9 0.3 10 86 16.0/1 10 4 10 0.2 20 83 8.5/1(1/3.7)

[0190] Note: An additional experiment was performed using ketone 4 andsubstrate 9 in which the catalyst loading and reaction time were 0.2 and12 h, respectively. The subsequent epoxidation reaction resulted in an89% yield and a β/α-epoxide ratio of 11.4/1. TABLE 2 Stereoselectiveepoxidation of 3α-substituted Δ⁵-steroids by dioxiranes generated insitu^(a) catalyst reaction loading time yield β/α-epoxide entry ketonesubstrate (equivalent) (h)^(b) (%)^(c) ratio^(d,e) 1 1^(f) 11 20 2 9019:1 2 2 11 0.05 2 93 5:1 3 3 11 0.1 3.5 91 4:1 4 4 11 0.2 8 92 90:1 5 212 0.05 4 82 72:1(2:1) 6 4 12 0.3 18 84^(g) >99:1 7 1^(e) 13 20 186 >99:1 8 2 13 0.05 2 94 96:1 9 3 13 0.1 1.5 93 49:1 10 4 13 0.3 1284 >99:1 11 2 14 0.05 3.5 95 >99:1 12 4 14 0.3 18 86^(h) >99:1 13 2 150.05 2 88 79:1 (1:1) 14 4 15 0.2 10 83 86:1 15 2 16 0.05 3 95 91:1 16 416 0.2 12 82 >99:1 17 2 17 0.05 1 91 84:1 (1:1) 18 4 17 0.2 15 81 66:119 2 18 0.05 3.5 96 92:1 20 4 18 0.2 12 84 61:1 21 2 19 0.05 2 92 51:122 4 19 0.2 9 91 50:1 23 2 20 0.05 2 92 85:1(1:1) 24 4 20 0.3 12 82 62:1

[0191] TABLE 3 Stereoselective epoxidation of 3α-substituted Δ⁵-steroidscatalyzed by acctonc. catalyst loading reaction time yield β/α-epoxideEntry substrate (equivalent) (h)^(b) (%)^(c) ratio^(d,e) 1 11 20 5 903:1 (1:9.5) 2 13 20 5 94 >99:1^([f]) (1:1) 3 14 20 6 93 >99:1 (1:1) 4 1620 3.5 93 >99:1 (1:1) 5 18 20 6 92 >99:1 (1:1) 6 19 20 5 91 43:1 (1:1)

What is claimed is:
 1. A method of producing mostly 5β,6β-epoxides ofsteroids from Δ⁵-unsaturated steroids by an epoxidation reaction using aketone and an oxidizing agent under conditions effective to generateepoxides. wherein said ketone is selected from compounds of genericformula I.

R₁ or R₄ in formula (I) is selected from alkyl, halogenated alkyl, aryl,OR (where R=H, alkyl or aryl), OCOR (where R=H, alkyl or aryl), OCOOR(where R=H alkyl or aryl), OCOOCH₂R (where R=aryl), OCONR₁R₂ (where R₁or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkyl or aryl),and halogen; R₂ or R₃ in formula (I) is selected from H, alkyl,halogenated alkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H,alkyl or aryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl),OCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ orR₃=alkyl or aryl), and halogen; R₅, R₆, R₇ or R₈ in formula (I) isselected from H, alkyl, halogenated alkyl, aryl, COOR (where R=H, alkylor aryl), and CONR₁R₂ (where R₁ or R₂=H, alkyl or aryl); R₉ or R₁₀ informula (I) is selected from alkyl, halogenated alkyl, and aryl; and Ain formula (I) is selected from halogen, OTf, BF₄, OAc, NO₃, BPh₄, PF₆,and SbF₆.
 2. The method of claim 1 wherein said oxidizing reagent isselected from the group consisting of potassium peroxomonosulfate,sodium hypochlorite, sodium perborate, hydrogen peroxide, and peracids.3. The method of claim 2 wherein said epoxidation reaction is carriedout using potassium peroxomonosulfate as an oxidizing agent.
 4. Themethod of claim 1 wherein said epoxidation reaction is carried out in ahomogeneous solvent system containingdimethoxymethane-acetonitrile-water, acetonitrile-water, acetone-water,dioxane-water, dimethoxyethane-water, tetrahydrofuran-water, or abiphasic solvent system containing dichloromethane-water,chloroform-water, benzene-water, toluene-water, dimethoxymethane-water,or diethylether-water, or mixtures thereof.
 5. The method of claim 1wherein said epoxidation reaction is carried out at a temperature withinthe range from about −10° C. to about 40° C.
 6. The method of claim 5wherein said epoxidation reaction is carried out at room temperature. 7.The method of claim 1 wherein said epoxidation reaction is carried outat a pH within the range from about 7.0 to about 12.0.
 8. The method ofclaim 7 wherein said pH is within the range from about 7.0 to about 7.5.9. The method of claim 7 wherein said pH is controlled by using apH-stat or a buffer.
 10. The method of claim 9 wherein said buffer isselected from the solutions consisting of sodium bicarbonate, sodiumcarbonate, sodium borate, sodium hydrogenphosphate, sodiumdihydrogenphosphate, sodium hydroxide, potassium hydrogenphosphate,potassium dihydrogenphosphate, potassium bicarbonate, potassiumcarbonate, potassium hydroxide, or mixtures thereof.
 11. The method ofclaim 1 wherein said epoxidation reaction provides said epoxides in atleast about 5:1 β/α-epoxide ratio.
 12. A method of producing mostly5β,6α-epoxides of steroids from Δ⁵-unsaturated steroids having asubstituent at the 3β-position by an epoxidation reaction using a ketoneand an oxidizing agent under conditions effective to generate epoxides.13. The method of claim 12 wherein said substituent is selected from OR(where R=H, alkyl or aryl), O(CH₂)_(n)OR (where n=1, 2 or 3, R=H, alkylor aryl), O(CH₂)_(m)SO_(n)R (where n=1, 2 or 3; n=0, 1 or 2; R=H, alkylor aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkyl or aryl), OSO_(n)R (wheren=0, 1 or 2; R=H, alkyl or aryl), OCO_(n)R (where n=1 or 2; R=H, alkylor aryl), OCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl), OPO_(n)R (wherewhere n=2 or 3; R=alkyl or aryl), NR₁R₂ (where R₁ or R₂=H, alkyl oraryl), NR₁CO_(n)R₂ (where n=1 or 2; R₁ or R₂=H, alkyl or aryl),NR₁CONR₂R₃ (where R₁, R₂ or R₃=H, alkyl or aryl), NR₁SO_(n)R₂ (where n=1or 2; R₁=H, alkyl or aryl, R₂=alkyl or aryl), NPhth (Phth=phthaloylgroup), ⁺NR₁R₂R₃ (where R₁, R₂, or R₃=H, alkyl or aryl), SiR₁R₂R₃ (whereR₁, R₂, or R₃=H, alkyl or aryl), SO_(n)R (where n=0, 1 or 2; R=H, alkylor aryl), SCO_(n)R (where n=1 or 2; R=H, alkyl or aryl), halogen, CN,NO₂, alkyl, aryl, COOR (where R=H, alkyl or aryl), and CONR₁R₂ (where R₁or R₂=H, alkyl or aryl).
 14. The method of claim 12 wherein saidΔ⁵-unsaturated steroid having a substituent at the 3α-position isselected from the group consisting of Δ⁵-unsaturated steroids having aketal derivative of ketone group or a thioketal derivative of ketonegroup at the 3-position.
 15. The method of claim 12 wherein said ketoneis selected from the group consisting of compounds of generic formulaII, III, IV, and V wherein

R₁, R₂, R₃, or R₄ in formula (II) is selected from H, alkyl, halogenatedalkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H, alkyl oraryl), OCOOR (where R=alkyl or aryl), OCONR₁R₂ (where R₁ or R₂=H, alkylor aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkyl or aryl), and halogen; R₅,R₆, R₇, R₈, R₉ or R₁₀ in formula (II) is selected from H, alkyl,halogenated alkyl, aryl, COOR (where R=H, alkyl or aryl), and CONR₁R₂(where R₁ or R₂=H, alkyl or aryl); A in formula (II) is selected fromhalogen, OTf, BF₄, OAc, NO₃, BPh₄, PF₆, and SbF₆;

X in formula (III) is selected from (CR₁R₂)_(n) (where n=1, 2, 3, 4, or5; R₁ or R₂=H, alkyl or aryl), O, S, SO, SO₂, and NR (where R=H, alkylor aryl); R₁₁, R₁₂, R₁₃, or R₁₄ in formula (III) is selected from H,alkyl, halogenated alkyl, aryl, OR (where R=H, alkyl or aryl), OCOR(where R=H, alkyl or aryl), OCOOR (where R=alkyl or aryl), OCONR₁R₂(where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkylor aryl), and halogen; R₁₅, R₁₆, R₁₇, or R₁₈ in formula (III) isselected from H, alkyl, halogenated alkyl, aryl, COOR (where R=H, alkylor aryl), and CONR₁R₂ (where R₁ or R₂=H, alkyl or aryl);

R₁₉ or R₂₀ in formula (IV) is selected from alkyl, halogenated alkyl,aryl, CR₁R₂OCOR₃ (where R₁, R₂ or R₃=H, alkyl or aryl), CR₁R₂OCOOR₃(where R₁ or R₂=H, alkyl or aryl; R₃=alkyl or aryl), CR₁R₂NR₃COOR₄(where R₁, R₂ or R₃=H, alkyl or aryl, R₄=alkyl or aryl), CR₁R₂NR₃COR₄(where R₁, R₂, R₃ or R₄=H, alkyl or aryl), and CR₁R₂NR₃SO₂R₄ (where R₁,R₂ or R₃=H, alkyl or aryl; R₄=alkyl or aryl); and

Y in formula (V) is selected from H, alkyl, halogenated alkyl, aryl,NO₂, CN, F, Cl, Br, I, COOR (where R=H or alkyl), OR (where R=H, alkylor aryl), OSO₂R (where R=H, alkyl or aryl), OSOR (where R=H, alkyl oraryl), OSR (where R=H, alkyl or aryl), SO₂R (where R=H, alkyl or aryl),SO₃R (where R=H, alkyl or aryl), SOON R₁R₂ (where R₁ or R₂=H, alkyl oraryl), NR₁SOOR₂ (where R₁=H, alkyl or aryl; R₂=alkyl or aryl), NR₁SOR₂(where R₁=H, alkyl or aryl; R₂=alkyl or aryl), CR₁R₂OR₃ (where R₁, R₂ orR₃=H, alkyl or aryl), CR₁(OR₂)₂ (where R₁=H or alkyl; R₂=alkyl), CF₃,CF₂CF₃, OTf, OTs, OCOR (where R=H, alkyl or aryl), and OSiR₁R₂R₃ (whereR₁, R₂ or R₃=alkyl or aryl).
 16. The method of claim 12 wherein saidepoxidation reaction is carried out in a homogeneous solvent systemcontaining dimethoxymethane-acetonitrile-water, acetonitrile-water,acetone-water, dioxane-water, dimethoxyethane-water,tetrahydrofuran-water, or a biphasic solvent system containingdichloromethane-water, chloroform-water, benzene-water, toluene-water,dimethoxymethane-water, or diethylether-water, or mixtures thereof. 17.The method of claim 12 wherein said oxidizing reagent is selected fromthe group consisting of potassium peroxomonosulfate, sodiumhypochlorite, sodium perborate, hydrogen peroxide, and peracids.
 18. Themethod of claim 17 wherein said epoxidation reaction is carried outusing potassium peroxomonosulfate as an oxidizing agent.
 19. The methodof claim 12 wherein said epoxidation reaction is carried out at atemperature within the range from about −10° C. to about 40° C.
 20. Themethod of claim 19 wherein said epoxidation reaction is carried out atroom temperature.
 21. The method of claim 12 wherein said epoxidationreaction is carried out at a pH within the range from about 7.0 to about12.0.
 22. The method of claim 21 wherein said pH is within the rangefrom about 7.0 to about 7.5.
 23. The method of claim 21 wherein said pHis controlled by using a pH-stat or a buffer.
 24. The method of claim 23wherein said buffer is selected from the solutions consisting of sodiumbicarbonate, sodium carbonate, sodium borate, sodium hydrogenphosphate,sodium dihydrogenphosphate, sodium hydroxide, potassiumhydrogenphosphate, potassium dihydrogenphosphate, potassium bicarbonate,and potassium carbonate, potassium hydroxide, and mixtures thereof. 25.The method of claim 12 wherein said epoxidation reaction provides saidepoxides in at least about 5:1 β/α-epoxide ratio.
 26. A method ofproducing mostly 5β,6α-epoxides of steroids from Δ⁵-unsaturated steroidsby an epoxidation reaction using a dioxirane under conditions effectiveto generate epoxides, wherein said dioxirane is selected from compoundsof generic formula VI,

R₁ or R₄ in formula (VI) is selected from alkyl, halogenated alkyl,aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H, alkyl or aryl),OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl), OCONR₁R₂ (whereR₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkyl oraryl), and halogen; R₂ or R₃ in formula (VI) is selected from H, alkyl,halogenated alkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H,alkyl or aryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl),OCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ orR₃=alkyl or aryl), and halogen; R₅, R₆, R₇ or R₈ in formula (VI) isselected from H, alkyl, halogenated alkyl, aryl, COOR (where R=H, alkylor aryl), and CONR₁R₂ (where R₁ or R₂=H, alkyl or aryl); R₉ or R₁₀ informula (VI) is selected from alkyl, halogenated alkyl, and aryl; and Ain formula (VI) is selected from halogen, OTf, BF₄, OAc, NO₃, BPh₄, PF₆,and SbF₆.
 27. The method of claim 26 wherein said dioxirane is generatedin situ from a ketone and an oxidizing agent selected from potassiumperoxomonosulfate, sodium hypochlorite, sodium perborate, hydrogenperoxide, and peracids. wherein said ketone is selected from compoundsof generic formula I,

R₁ or R₄ in formula (I) is selected from alkyl, halogenated alkyl, aryl,OR (where R=H, alkyl or aryl), OCOR (where R=H, alkyl or aryl), OCOOR(where R=alkyl or aryl), OCOOCH₂R (where R=aryl), OCONR₁R₂ (where R₁ orR₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkyl or aryl), andhalogen; R₂ or R₃ in formula (I) is selected from H, alkyl, halogenatedalkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H, alkyl oraryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl), OCONR₁R₂(where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkylor aryl), and halogen; R₅, R₆, R₇ or R₈ in formula (I) is selected fromH, alkyl, halogenated alkyl, aryl, COOR (where R=H, alkyl or aryl), andCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl); R₉ or R₁₀ in formula (I) isselected from alkyl, halogenated alkyl, and aryl; and A in formula (I)is selected from halogen, OTf, BF₄, OAc, NO₃, BPh₄, PF₆, and SbF₆. 28.The method of claim 26 wherein said epoxidation reaction is carried outin a solvent selected from acetonitrile, dimethoxymethane, acetone,dioxane, dimethoxyethane, tetrahydrofuran, dichloromethane, chloroform,benzene, toluene, diethylether, water, and mixtures thereof.
 29. Themethod of claim 26 wherein said epoxidation reaction is carried out at atemperature within the range from about −40° C. to about 40° C.
 30. Themethod of claim 26 wherein said epoxidation reaction is carried out at apH within the range from about 7.0 to about 12.0.
 31. The method ofclaim 26 wherein said epoxidation reaction provides said epoxides in atleast about 5:1 β/α-epoxide ratio.
 32. A method of producing mostly5β,6α-epoxides of steroids from Δ⁵-unsaturated steroids having asubstituent at the 3α-position by an epoxidation reaction using adioxirane under conditions effective to generate epoxides.
 33. Themethod of claim 32 wherein said substituent is selected from OR (whereR=H, alkyl or aryl), O(CH₂)_(n)OR (where n=1, 2 or 3, R=H, alkyl oraryl), O(CH₂)_(m)SO_(n)R (where n=1, 2 or 3; n=0, 1 or 2; R=H, alkyl oraryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkyl or aryl), OSO_(n)R (wheren=0, 1 or 2; R=H, alkyl or aryl), OCO_(n)R (where n=1 or 2; R=H, alkylor aryl), OCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl), OPO_(n)R (wherewhere n=2 or 3; R=alkyl or aryl), NR₁R₂ (where R₁ or R₂=H, alkyl oraryl), NR₁CO_(n)R₂ (where n=1 or 2; R₁ or R₂=H, alkyl or aryl),NR₁CONR₂R₃ (where R₁, R₂ or R₃=H, alkyl or aryl), NR₁SO_(n)R₂ (where n=1or 2; R₁=H, alkyl or aryl, R₂=alkyl or aryl), NPhth (Phth=phthaloylgroup), ⁺NR₁R₂R₃ (where R₁, R₂, or R₃=H, alkyl or aryl), SiR₁R₂R₃ (whereR₁, R₂, or R₃=H, alkyl or aryl), SO_(n)R (where n=0, 1 or 2; R=H, alkylor aryl), SCO_(n)R (where n=1 or 2; R=H, alkyl or aryl), halogen, CN,NO₂, alkyl, aryl, COOR (where R=H, alkyl or aryl), and CONR₁R₂ (where R₁or R₂=H, alkyl or aryl).
 34. The method of claim 32 wherein saidΔ⁵-unsaturated steroid having a substituent at the 3α-position isselected from the group consisting of Δ⁵-unsaturated steroids having aketal derivative of ketone group or a thioketal derivative of ketonegroup at the 3-position.
 35. The method of claim 32 wherein saiddioxirane is selected from the group consisting of compounds of genericformula VII, VIII, IX and X.

R₁, R₂, R₃, or R₄ in formula (VII) is selected from H, alkyl,halogenated alkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H,alkyl or aryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl),OCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ orR₃=alkyl or aryl), and halogen; R₅, R₆, R₇, R₈, R₉ or R₁₀, in formula(VII) is selected from H, alkyl, halogenated alkyl, aryl, COOR (whereR=H, alkyl or aryl), and CONR₁R₂ (where R₁ or R₂=H, alkyl or aryl); A informula (VII) is selected from halogen, OTf, BF₄, OAc, NO₃, BPh₄, PF₆,and SbF₆;

X in formula (VIII) is selected from (CR₁R₂)_(n), (where n=1, 2, 3, 4,or 5; R₁ or R₂=H, alkyl or aryl), O, S, SO, SO₂, and NR (where R=H,alkyl or aryl); R₁₁, R₁₂, R₁₃, or R₁₄ in formula (VIII) is selected fromH, alkyl, halogenated alkyl, aryl, OR (where R=H, alkyl or aryl), OCOR(where R=H, alkyl or aryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R(where R=aryl), OCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃(where R₁, R₂ or R₃=alkyl or aryl), and halogen; R₁₅, R₁₆, R₁₇, or R₁₈in formula (VIII) is selected from H, alkyl, halogenated alkyl, aryl,COOR (where R=H, alkyl or aryl), and CONR₁R₂ (where R₁ or R₂=H, alkyl oraryl);

R₁₉ or R₂₀ in formula (IX) is selected from alkyl, halogenated alkyl,aryl, CR₁R₂OCOR₃ (where R₁, R₂ or R₃=H, alkyl or aryl), CR₁R₂OCOOR₃(where R₁ or R₂=H, alkyl or aryl; R₃=alkyl or aryl), CR₁R₂NR₃COOR₄(where R₁, R₂ or R₃=H, alkyl or aryl, R₄=alkyl or aryl), CR₁R₂NR₃COR₄(where R₁, R₂, R₃ or R₄=H, alkyl or aryl), CR₁R₂NR₃SO₂R₄ (where R₁, R₂or R₃=H, alkyl or aryl; R₄=alkyl or aryl); and

Y in formula (X) is selected from H, alkyl, halogenated alkyl, aryl,NO₂, CN, F, Cl, Br, I, COOR (where R=H or alkyl), OR (where R=H, alkylor aryl), OSO₂R (where R=H, alkyl or aryl), OSOR (where R=H, alkyl oraryl), OSR (where R=H, alkyl or aryl), SO₂R (where R=H, alkyl or aryl),SO₃R (where R=H, alkyl or aryl), SOON R₁R₂ (where R₁ or R₂=H, alkyl oraryl), NR₁SOOR₂ (where R₁=H, alkyl or aryl; R₂=alkyl or aryl), NR₁SOR₂(where R₁=H, alkyl or aryl; R₂=alkyl or aryl), CR₁R₂OR₃ (where R₁, R₂ orR₃=H, alkyl or aryl), CR₁(OR₂)₂ (where R₁=H or alkyl; R₂=alkyl), CF₃,CF₂CF₃, OTf, OTs, OCOR (where R=H, alkyl or aryl), and OSiR₁R₂R₃ (whereR₁, R₂ or R₃=alkyl or aryl).
 36. The method of claim 32 wherein saiddioxirane is generated in situ from a ketone and an oxidizing agentselected from potassium peroxomonosulfate, sodium hypochlorite, sodiumperborate, hydrogen peroxide, and peracids.
 37. The method of claim 36wherein said ketone is selected from the group consisting of compoundsof generic formula II, III, IV, and V,

R₁, R₂, R₃, or R₄ in formula (II) is selected from H, alkyl, halogenatedalkyl, aryl, OR (where R=H, alkyl or aryl), OCOR (where R=H, alkyl oraryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R (where R=aryl), OCONR₁R₂(where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃ (where R₁, R₂ or R₃=alkylor aryl), and halogen; R₅, R₆, R₇, R₈, R₉ or R₁₀ in formula (II) isselected from H, alkyl, halogenated alkyl, aryl, COOR (where R=H, alkylor aryl), and CONR₁R₂ (where R₁ or R₂=H, alkyl or aryl); A in formula(II) is selected from halogen, OTf, BF₄, OAc, NO₃, BPh₄, PF₆, and SbF₆;

X in formula (III) is selected from (CR₁R₂)_(n) (where n=1, 2, 3, 4, or5; R₁ or R₂=H, alkyl or aryl), O, S, SO, SO₂, and NR (where R=H, alkylor aryl); R₁₁, R₁₂, R₁₃, or R₁₄ in formula (III) is selected from H,alkyl, halogenated alkyl, aryl, OR (where R=H, alkyl or aryl), OCOR(where R=H, alkyl or aryl), OCOOR (where R=alkyl or aryl), OCOOCH₂R(where R=aryl), OCONR₁R₂ (where R₁ or R₂=H, alkyl or aryl), OSiR₁R₂R₃(where R₁, R₂ or R₃=alkyl or aryl), and halogen; R₁₅, R₁₆, R₁₇, or R₁₈in formula (III) is selected from H, alkyl, halogenated alkyl, aryl,COOR (where R=H, alkyl or aryl), and CONR,R₂ (where R₁ or R₂=H, alkyl oraryl);

R₁₉ or R₂₀ in formula (IV) is selected from alkyl, halogenated alkyl,aryl, CR₁R₂OCOR₃ (where R₁, R₂ or R₃=H, alkyl or aryl), CR₁R₂OCOOR₃(where R₁ or R₂=H, alkyl or aryl; R₃=alkyl or aryl), CR₁R₂NR₃COOR₄(where R₁, R₂ or R₃=H, alkyl or aryl, R₄=alkyl or aryl), CR₁R₂NR₃COR₄(where R₁, R₂, R₃ or 4=H, alkyl or aryl), CR₁R₂NR₃SO₂R₄ (where R₁, R₂ orR₃=H, alkyl or aryl; R₄=alkyl or aryl); and

Y in formula (V) is selected from H, alkyl, halogenated alkyl, aryl,NO₂, CN, F, Cl, Br, I, COOR (where R=H or alkyl), OR (where R=H, alkylor aryl), OSO₂R (where R=H, alkyl or aryl), OSOR (where R=H, alkyl oraryl), OSR (where R=H, alkyl or aryl), SO₂R (where R=H, alkyl or aryl),SO₃R (where R=H, alkyl or aryl), SOON R₁R₂ (where R₁ or R₂=H, alkyl oraryl), NR₁SOOR₂ (where R₁=H, alkyl or aryl; R₂=alkyl or aryl), NR₁SOR₂(where R₁=H, alkyl or aryl; R₂=alkyl or aryl), CR₁R₂OR₃ (where R₁, R₂ orR₃=H, alkyl or aryl), CR₁(OR₂)₂ (where R₁=H or alkyl; R₂=alkyl), CF₃,CF₂CF₃, OTf, OTs, OCOR (where R=H, alkyl or aryl), and OSiR₁R₂R₃ (whereR₁, R₂ or R₃=alkyl or aryl).
 38. The method of claim 32 wherein saidepoxidation reaction is carried out in a solvent selected fromacetonitrile, dimethoxymethane, acetone, dioxane, dimethoxyethane,tetrahydrofuran, dichloromethane, chloroform, benzene, toluene,diethylether, water and mixtures thereof.
 39. The method of claim 32wherein said epoxidation reaction is carried out at a temperature withinthe range from about −40° C. to about 40° C.
 40. The method of claim 32wherein said epoxidation reaction is carried out at a pH within therange from about 7.0 to about 12.0.
 41. The method of claim 32 whereinsaid epoxidation reaction provides said epoxides in at least about 5:1β/α-epoxide ratio.
 42. A method comprising: producing mostly5β,6β-epoxides of steroids by epoxidation reactions of Δ⁵-unsaturatedsteroids of generic formula XI catalyzed by ketones of generic formulaXII, wherein

X₁ in formula (XI) is selected from H, OR (where R=H or alkyl),OCH₂OCH₃, OCOR (where R=alkyl or aryl), OSiR₁′R₂′R₃′ (where R₁′, R₂′ orR₃′=alkyl or aryl), halogen, CN, alkyl, aryl, and COOR (where R=H, alkylor aryl); R₁in formula (XI) is selected from H, OR (where R=H or alkyl),OCOR (where R=alkyl or aryl), OCH₂OCH₃, halogen, CF₃, and CF₂CF₃; R₂ andR₃ in formula (XI) are each selected from the group consisting of H,alkyl, aryl, halogen, OR (where R=H or alkyl), OCOR (where R=alkyl oraryl), OSiR₁′R₂′R₃′ (where R₁′, R₂′ or R₃′=alkyl or aryl), COR (whereR=alkyl), COCH₂OR (where R=H or alkyl), COCH₂OCOR (where R=alkyl oraryl), COCH₂F, COOR (where R=H or alkyl), C(OCH₂CH₂O)R (where R=alkyl),C(OCH₂CH₂O)CH₂ OR (where R=H or alkyl), C(OCH₂CH₂O)CH₂OCOR (whereR=alkyl or aryl), and C(OCH₂CH₂O)CH₂F; or, are selected from the groupconsisting of O, OCH₂CH₂O, and OCH₂CH₂CH₂O; R₄ in formula (XI) isselected from H, C₁-C₄ alkyl, halogen, OR (where R=H or alkyl), OCOR(where R=alkyl or aryl), and OSiR₁′R₂′R₃′ (where R₁′, R₂′ or R₃′=alkylor aryl); R₅ in formula (XI) is selected from H, C₁-C₄ alkyl, halogen,OR (where R=H or alkyl), OCOR (where R=alkyl or aryl), and OSiR₁′R₂′R₃′(where R₁′, R₂′ or R₃′=alkyl or aryl); R₆ in formula (XI) is selectedfrom H, halogen, OR (where R=H or alkyl), and OCOR (where R=alkyl oraryl); R₇ in formula (XI) is selected from H, halogen, OR (where R=H oralkyl), and OCOR (where R=alkyl or aryl);

R₁₅ and R₁₆ in formula (XII) are each selected from alkyl and aryl; R₁₇and R₁₈ in formula (XII) are each selected from H, alkyl, aryl, COOR(where R=H, alkyl or aryl), and CONR₁R₂ (where R₁ or R₂=H, alkyl oraryl); R₁₉ and R₂₀ in formula (XII) are each selected from C₁-C₄ alkyl,halogenated alkyl, and halogen; and A in formula (XII) is selected fromOTf, BF₄, OAc, NO₃, BPh₄, PF₆, and SbF₆.
 43. The method of claim 42wherein said C₁-C₄ alkyl is selected from the group consisting ofmethyl, ethyl, normal-propyl, iso-propyl, normal-butyl, iso-butyl,sec-butyl, and tert-butyl; and said aryl selected from the groupconsisting of phenyl, substituted phenyl, naphthyl, and substitutednaphthyl groups.
 44. The method of claim 42 wherein said epoxidationreactions are carried out in a homogeneous solvent system selected fromthe group consisting of dimethoxymethane-acetonitrile-water,acetonitrile-water, acetone-water, dioxane-water, dimethoxyethane-water,tetrahydrofuran-water, and mixtures thereof.
 45. The method of claim 42wherein said epoxidation reactions are carried out in a biphasic solventsystem selected from the group consisting of dichloromethane-water,chloroform-water, benzene-water, toluene-water, dimethoxymethane-water,or diethylether-water, and mixtures thereof.
 46. The method of claim 42wherein said oxidizing reagent is selected from the group consisting ofpotassium peroxomonosulfate, sodium hypochlorite, sodium perborate,hydrogen peroxide, and peracids.
 47. The method of claim 42 wherein saidepoxidation reactions are carried out at a temperature within the rangefrom about −10° C. to about 40° C.
 48. The method of claim 47 whereinsaid epoxidation reactions are carried out at room temperature.
 49. Themethod of claim 42 wherein said epoxidation reactions are carried out ata pH within the range from about 7.0 to about 12.0.
 50. The method ofclaim 49 wherein said pH is within the range from 7.0 to 7.5.
 51. Themethod of claim 49 wherein said pH is controlled by using a pH-stat or abuffer.
 52. The method of claim 51 wherein said buffer is selected fromthe group consisting of sodium bicarbonate, sodium carbonate, sodiumborate, sodium hydrogenphosphate, sodium dihydrogenphosphate, sodiumhydroxide, potassium hydrogenphosphate, potassium dihydrogenphosphate,potassium bicarbonate, potassium carbonate, potassium hydroxide, ormixtures thereof.
 53. A method comprising: producing mostly5β,6β-epoxides of steroids by epoxidation reactions of Δ⁵-unsaturatedsteroids of generic formula XIII catalyzed by ketones of generic formulaXIV, XV, XVI, and XVII, wherein

X₂ in formula (XIII) is selected from the group consisting of H, OR(where R=H or alkyl), OCH₂OCH₃, OCOR (where R=alkyl or aryl),OSiR₁′R₂′R₃′ (where R₁′, R₂′ or R₃′=alkyl or aryl), halogen, CN, alkyl,aryl, and COOR (where R=H, alkyl or aryl), and, X₃ in formula (XIII) isselected from the group consisting of OR (where R=H or alkyl), OCH₂OCH₃,OCOR (where R=alkyl or aryl), OSiR₁′R₂′R₃′ (where R₁′, R₂′ or R₃′=alkylor aryl), halogen, CN, NO₂, alkyl, and aryl; or, X₂ and X₃ in formula(XIII) are selected from the group consisting of O, OCH₂CH₂O, andOCH₂CH₂CH₂O; R₈ in formula (XIII) is selected from H, OR (where R=H oralkyl), OCOR (where R=alkyl or aryl), OCH₂OCH₃, halogen, CF₃, andCF₂CF₃; R₉ and R₁₀ in formula (XIII) are each selected from the groupconsisting of H, alkyl, aryl, halogen, OR (where R=H or alkyl), OCOR(where R=alkyl or aryl), OSiR₁′R₂′R₃′ (where R₁′, R₂′ or R₃′=alkyl oraryl), COR (where R=alkyl), COCH₂OR (where R=H or alkyl), COCH₂OCOR(where R=alkyl or aryl), COCH₂F, COOR (where R=H or alkyl), C(OCH₂CH₂O)R(where R=alkyl), C(OCH₂CH₂O)CH₂OR (where R=H or alkyl),C(OCH₂CH₂O)CH₂OCOR (where R=alkyl or aryl), and C(OCH₂CH₂O)CH₂F; or R₉and R₁₀ in formula (XIII) are selected from the group consisting of O,OCH₂CH₂O, and OCH₂CH₂CH₂O; R₁₁and R₁₂ in formula (XIII) are eachselected from the group consisting of H, C₁-C₄ alkyl, halogen, OR (whereR=H or alkyl), OCOR (where R=alkyl or aryl), and OSiR₁′R₂′R₃′ (whereR₁′, R₂′ or R₃′=alkyl or aryl); R₁₃ and R₁₄ in formula (XIII) are eachselected from the group consisting of H, halogen, OR (where R=H oralkyl), and OCOR (where R=alkyl or aryl);

R₁₅ or R₁₆ in formula (XIV) is selected from alkyl and aryl; R₁₇ or R₁₈in formula (XIV) is selected from H, alkyl, aryl, COOR (where R=H, alkylor aryl), and CONR₁R₂ (where R₁ or R₂=H, alkyl or aryl); R₁₉ or R₂₀ informula (XIV) is selected from H, C₁-C₄ alkyl, halogenated alkyl, andhalogen; and A in formula (XIV) is selected from OTf, BF₄, OAc, NO₃,BPh₄, PF₆, and SbF₆;

Y in formula (XV) is selected from CH₂, O, S, SO, SO₂, and NR (where R=Hor alkyl); R₂₁ or R₂₂ in formula (XV) is selected from H, alkyl, aryl,COOR (where R=H, alkyl or aryl), and CONR₁R₂ (where R₁ or R₂=H, alkyl oraryl); R₂₃ or R₂₄ in formula (XV) is selected from H, halogen, C₁-C₄alkyl, halogenated alkyl, and OCOR (where R=alkyl or aryl);

R₂₅ or R₂₆ in formula (XVI) is selected from C₁-C₄ alkyl, halogenatedalkyl, CH₂OCOR (where R=alkyl or aryl); and

Z in formula (XVII) is selected from H, C₁-C₄ alkyl, aryl, NO₂, CN, F,Cl, Br, I, COOR (where R=alkyl), CH₂OR (where R=H or alkyl), CH(OR)₂(where R=alkyl), CF₃, CF₂CF₃, OTf, OTs, OCOR (where R=alkyl or aryl),and OSiR₁′R₂′R₃′ (where R₁′, R₂′ or R₃′=alkyl or aryl).
 54. The methodof claim 53 wherein said C₁-C₄ alkyl is selected from the groupconsisting of methyl, ethyl, normal-propyl, iso-propyl, normal-butyl,iso-butyl, sec-butyl, and tert-butyl; and said aryl selected from thegroup consisting of phenyl, substituted phenyl, naphthyl, andsubstituted naphthyl groups.
 55. The method of claim 53 wherein saidepoxidation reactions are carried out in a homogeneous solvent systemselected from the group consisting ofdimethoxymethane-acetonitrile-water, acetonitrile-water, acetone-water,dioxane-water, dimethoxyethane-water, and tetrahydrofuran-water, andmixtures thereof.
 56. The method of claim 53 wherein said epoxidationreactions are carried out in a biphasic solvent system selected from thegroup consisting of dichloromethane-water, chloroform-water,benzene-water, toluene-water, dimethoxymethane-water, ordiethylether-water, and mixtures thereof.
 57. The method of claim 53wherein said oxidizing reagent is selected from the group consisting ofpotassium peroxomonosulfate, sodium hypochlorite, sodium perborate,hydrogen peroxide, and peracids.
 58. The method of claim 53 wherein saidepoxidation reactions are carried out at a temperature within the rangefrom about −10° C. to about 40° C.
 59. The method of claim 58 whereinsaid epoxidation reactions are carried out at room temperature.
 60. Themethod of claim 53 wherein said epoxidation reactions are carried out ata pH within the range from about 7.0 to about 12.0.
 61. The method ofclaim 60 wherein said pH is within the range from 7.0 to 7.5.
 62. Themethod of claim 60 wherein said pH is controlled by using a pH-stat or abuffer.
 63. The method of claim 62 wherein said buffer is selected fromthe group consisting of sodium bicarbonate, sodium carbonate, sodiumborate, sodium hydrogenphosphate, sodium dihydrogenphosphate, sodiumhydroxide, potassium hydrogenphosphate, potassium dihydrogenphosphate,potassium bicarbonate, potassium carbonate, potassium hydroxide, ormixtures thereof.